8-iso-13-polycarbonalkyl gonanes



Oct. 22, 1968 G. A- HUGHES ETAL 3,407,217

S-ISO-lE-POLYCARBONALKYL GONANES 3 Sheets-Sheet 1 Filed June 7, 1965 o zu INVENTORS GORDON A. HUGHES HERCHEL SMITH Oct. 22, 1968 HUGHES ETAL 3,407,217

8 ISO- 13 POLYCARBONALKYL GONANES Filed June 7, 1965 3 Sheets-Sheet 2 Aim" Mml Aw lm Or Acliylenlc Grlgnard Rouqom INVENTORS sonoou A. HUGHES Haney-Isl. sumar W #2 M Oct. 22, 1968 HUGHES ETAL 3,407,217

8 I SO- 15 -POLYCARBONALKYL GONANES Filed June 7, 1965 FIG. 7 CH 5 Sheets-Sheet 5 LiC-ECH FIG. 8 E 3 3 CH INVENTOR3' v GORDON A. HUGHES HERQHEL SMITH ATTORNEY United States Patent S-ISO-IB-POLYCARBONALKYL GONANES Gordon Alan Hughes, Wayne, Pa., and Herchel Smith, 500Chestnut Lane, Wayne, Pa. 19087; said Hughes assignor to said Smith l Original application Oct. 4, 1962, Ser. No. 228,384.

Dividedantl this application June 7, 1965, Ser. No. 461,909

Claims. (Cl. 260-3974) ABSTRACT OF THE DISCLOSURE This application is a division of co-pending application Ser. No. 228,384 filed Oct. 4, 1962, which is a continuation-in-part of applications Ser. No. 57.904 filed Sept. 23, 1960; Ser. No. 91,841 filed Feb. 24, 1961; Ser. No. 137,- 535 filed Sept. 12, 1961; Ser. No. 195,000 filed May 15, 1962; and Ser. No. 196,557 filed May 16, 1962, now abandoned.

This invention relates to compositions of matter classified in the art of chemistry as substituted unsaturated-8- isogonane derivatives, to intermediates therefor, and to processes for making and using such compositions.

In describing the invention, reference will be made in the following specification to the annexed drawings, wherein: 1

FIGURE 1 illustrated schematically the recation sequence for preparing'a l3 alkyl-8-isogon-5(10)-cue, specifically 136 ethyl 17a ethynyl-l7fi-hydroxy-8-isogon- 5(10)-en-3-one (XV).

FIGURE 2 illustrates schematically the hydrogenation of a 13-alkylgona-1,3,5(l0),8,l4-pentaene to prepare a 13-allcyl-8-isogona-1,3,5(10)-triene, specifically the conversion of 13fi-ethyl 3-methoxy-8-isogona-1,3,5(10)',8,14- pentaen-l7B-ol (XVI) to l3B-ethyl-3-methoxy-8-isogona 1,3,5(10)-triene-17;8-ol (XI).

FIGURE 3 illustrates schematically the hydrogenation of a l3-alkylgona-1,3,5(10),8,l4-pentaene in-two stages i.e. via a l3-alkylgona-l,3,5 10) ,S-tetraene, specifically the conversion of 13fi-ethyl-3-meth0xygona-1,3,5( l0),8,14- pentaen-l7-one (D() to 13/3-ethyl-3-methoxy-8-isogona-l, 3,5(10)-trien-l7-one (X). I

. FIGURE 4 illustrates schematically the reaction sequence for preparing a 17-alkynyl-13-alkyl-3-methoxy-8 isogona-1,3,5-triene from a 13-alkyl-3-methoxy-8-isogona 1,3,5 10)-trien-l7-one, specifically 13fi-ethyl-l7a-ethynyl 3-methoxy-8-isogona-1,3,5 10)-trien-17 8-ol (XVIII) from 135 ethyl 3 methoxy 8 isogona 1,3,5 (10) trien- 17-one (X).

FIGURE 5 illustrates schematically the mild acid. hydrolysis of a 13-alkylgona-2,5(10)-diene to a 13-alkylgon- 5 (10)ene, specifically 13B-ethyl-3 methoxy-8-isogen 2,5- (10)-dien-17fl-ol (XII) to 13fl-ethyl-l7B-hydroxy-8-isogen-5(10)-en,-3-one (XIX). i

FIGURE 6 illustrates schematically the mineral acid hydrolysis of a 13-alkyl-2-isogon-5(10)-ene, specifically 13fl-ethyl-3 -methoxy-8-isogona-2,5 10 -dien- 17,8-01 (XII) to l3fi-ethyl-l'Zfl-hydroxy-8-isogon-4-en-3-one (XIX) and 13B-ethyl-17fl-hydroxy-8-isogon-5(10)-en-3-one (XX).

' FIGURE 7 illustrates schematically the reaction sequence for preparing a 13-alkyl-l7-allrynyl 17/3-hydroxy- 8-isogon-5 (10)-ene-3-one for a 13-alkyl-3-alkoxy-8 isogona-2,5 (10)-dien-l7-ol, specifically 13,8-ethyl-17ut-ethynyl 17p-hydroxy-8-isogon-5(10)-en-3-one (XV) from ethyl-3-methoxy-8-isogon-2,5(10)-dien-17 3-ol (XII).

FIGURE 8 illustrates schematically the reaction sequence for preparing a mixture of a 13,17- dialkyl-8-isogon-4-en-l7-ol and a l3,17-dialkyl-8-isogon-5(l0)-en 17- 01 from a 13-a1kyl-17-alkynyl-3-alkoxy-8-isogona-1,3,5- (10)-trien-17-ol, specifically 13B,17a-diethyl-17 3-hydroxy- 8,-isogon-5(10)-en-3-one (XXVI) and 13fl,17a-diethyl- 17/3-hydroxy-8-isogon-4-en-3-one (XXVII) from 13,B-ethyl-17a-ethynyl 3 methoxy 8 isogona-l,3,5(10)-trien- -01 (XVIII).

The invention sought to be patented in a principal composition aspect is described as residing in the concept of a chemical compound having an unsaturated 8-isogonane nucleus and having attached thereto in the Iii-position a monovalent polycarbon-alkyl radical.

The tangible embodiments of the composition aspect of the invention possess the inherent general physical prop erties of being white crystalline solids, are substantially insoluble in water and are generally soluble in polar solvents such as dimethyacetamide. Examination of compounds produced according to the hereinafter described process reveals, upon ultraviolet and infrared spectographic analysis, spectral data supporting the molecular structures herein set forth. The aforementioned physical characteritics, taken together with the nature of the starting materials and the mode of synthesis, confirm the structure oft he compositions sought to be patented.

The tangible embodiments of the invention posses the inherent applied use characteristics of exerting qualitatively varying hormonal etfects in animals as evidenced by pharmacological evalution according to standard test procedures. Such tangible embodiments show estrogenic, androgenic, anti-estrogenic, progestational, blood lipid effects, and anabolic actions, salt retention, salt excretion and central nervous system efiects. This finding indicates their usefulness in the treatment of female hypogonadism. amenorrhea, dysmenorrhea, ovulation block and contraception, functional uterine bleeding, acne, osteoporosis, infertility, pregnancy maintenance, habitual abortion, weight gain and nitrogen retention, growth stimulation, post operative recovery, healing of wounds, and healing of burns. In particular it has been established that alterations of the natural steroid structure made possible by our discovery result not merely in a change of degree of hormonal activity but, as result of the separation .of types of hormonal activity, alter in an unexpected way its basic nature so that a desirable hormone effect is maximized and an undesirable hormone effect is minimized.

In addition to their inherent applied use characteristics, the intermediate compositions of this invention are useful in practicing the process aspect of the present invention in the making of the principal 8-isogonane compositions of the invention according to the sequence of reactions described herein.

The invention sought to be patented in a second composition aspect is described as residing in the concept of an 8-isogona-1,3,5-(10)-triene nucleus having attached thereto in the 13-position a monovalent polycarbon-alkyl radical (FIGURE 1, X, XI; FIGURE 4, XVIII; FIGURE 8, XXIV).

' The tangible embodiments of said second composition aspect possess the use characteristic of exerting hormonal effects as evidenced by standard test procedures. Furthermore said tangible embodiments of said composition aspect possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal eifects as evidenced by standard test procedures.

The invention sought to be patented in a third composition aspect is described as residing in the concept of an 8-isogona-2,5 (10)-diene nucleus having attached thereto in the 13-position a monovalent polycarbon alkyl radical (FIGURE 1, XII, XII and XIV; FIGURE 8, XXV).

The tangible embodiments of said third composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. Furthermore said tangible embodiments possess the use characteristic of being intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures. p

The invention sought to be patented in a fourth composition aspect is described as residing in the concept of a compound having an 8-isogon-5(10)-ene nucleus having attached thereto in the l3-position a monovalent polycarbonalkyl radical (FIGURE 1, XV; FIGURE 5, XIX).

The tangible embodiments of said fourth composition aspect possess the use characteristic of exerting varying hormone effects in animals as evidenced by pharmacological evaluation including estrogenic and lipid shiiting effects. Furthermore said tangible embodiments'of said fourth composition aspect possess the use characteristic of being important intermediates for the preparation of compositions exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a fifth composition aspect is described as residing in the concept of a mixture of a compound having an 8-isogon-5(10)-ene nucleus and the correspondingly substituted compound having an 8-isogon-4-ene nucleus, both of said gonenes having attached thereto in their 13-positio'ns a monovalent polycarbon alkyl radical (FIGURE 6; XIX and XX; FIGURE 8, XXVI and XXVII).

The tangible embodiments of said fifth composition aspect possess the use characteristic of exerting hormonal effects as evidenced by standard test procedures.

The invention sought to be patented in a sub-generic composition aspect is described as residing in the concept of a 13-po1ycarbonalkyl-8-isogona-1,3,5(10)-trien-17-ol (FIGURE 1; XI), of which a specific embodiment, 13B- ethyl-3-meth0xy-8-isogona-1,3,5(l0)-trien-17;8-ol is hereinafter described.

The tangible embodiments of said sub-generic composition aspect possess the use characteristic of varying hormone effects in animals as evidenced by pharmacological evaluation by standard test procedures. In clinical tests, said specific embodiment has been eifective in the control of post-menopausal syndrome.

The invention sought to be patented in a second subgeneric composition aspect is described as residing in the concept of 17-alkynyl-l3-polycarbonalkyl-8-isogona-l,3,5 (l)-trien-17-ol (FIGURE 4; XVIII) of which a specific embodiment, 135 ethyl-17a-ethynyl-8-isogona-1,3,5(10)- trien-17B-ol, is hereinafter described.

The tangible embodiments of said second sub-generic composition aspect possess the use characteristic of varying hormone effects in animals, as evidenced by pharmacological evaluation by standard test procedures, and in particular have demonstrated a high pituitary blocking activity, coupled with an unexpected separation of activities.

The invention sought to be patented in a third subgeneric composition aspect is described as residing in the concept of a .17 alkynyl 13-polycarbonalkyl-8-isogon-5 ()-ene (FIGURE 1; XV) of which a specific embodiment, 135 ethyl-17a-ethynyl-8-isogon-5 (10)-en-17;8-o1-3- one, is hereinafter described.

The tangible embodiments of said third sub-generic composition aspect possess the use characteristic of varying hormone effects in animals, as evidenced by pharmacological evaluation by standard test procedures, and in particular in certain instances pituitary blocking efi'ects accompanied by unexpected separation of activities.

The invention sought to be patented in a process aspect, is described as residing in the concept of catalytically hydrogenating a compound having a gona-1,3,5(10), 8,14-

pentaen-17-one nucleus in the presence of a solvent to obtain the corresponding compound having an 8-isogona- 1,3,5 (10)-t-rien-l7-one nucleus, i.e., a g0na-1,3,5 (10)- trien-17-one in which the 8-position hydrogen is in an a configuration instead of the p configuration of the natural gonane structure (XX).

wThe' manner and process of making and using' the invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows: I U

Referring now to FIGURE 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13 3-ethyl-17a-ethynyl- 17/3-hydroxy-8-isogon-5(10)-en-3-one is illustrated. 3- (m- Methoxyphenyl) propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3- (m-me'thoxyphenyDpropyl bromide (II). This halogen compound (II) dissolved to tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5 (m-methoxyphenyl) 1 pentyne (III). CompoundIII is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride at 70 C. for about 12 hours, whereby the is obtained l-diethylamino-fi-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1- diethylamine on distillation to give the vinyl ketone 6-(.m-methoxyphenyl)-l-hexan-S-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(mmethoxyphenyl) 3 oxoheXyl] 1,3 cyclopentanedione (VIII).

Compound VIII is then cyclodehydrated at the reflux temperature of a solvent, such as benzene, in the presence of a dehydrating acid, such as p-toluene sulfonic acid, to effect simultaneous ring closures to give the tetracyclic compound 13,9 ethyl 3 methoxygona-1,3,5(10),8,14- pentaen-l7-0ne (IX). The 8 and 14-unsaturation of Compound IX is then hydrogenated in the presence of a metal catalyst, such as 10% palladized carbon, to form ethyl 3 methoxy-8-isogona-l,3,5(l0)-trien-l7'one (X).

Reduction of the carbonyl group of Compound X to a.

hydroxyrnethylene group, as with sodium borohydride in an alcohol, then gives 13fl-ethyl-3-methoxy-8 isogona- 1,3,5 (10)-trien-17;8-ol XI, which, by alkali metal reduction. in liquid ammonia in the presence of a proton donor such as ethanol (Birch reduction), is converted to '135- ethyl 3 methoxy 8 isogon-2,5(10)-dien-17;3-ol (XII) which, on Oppenauer oxidation, gives l3fl-ethyl-3-methoxygona-2,5(l0)-dien-l7-one (XIII). Ethynyla'tion at the 17-position of compound XII with lithium acetyl ide in dimethylacetamide gives 1 3B-ethyl-17d-ethynyl-3- methoxy-8-isogona2,5 (10)-dien-l7}3-ol XIV. By acid hydrolysis with a weak acid such as oxalic acid compound XIV is converted to compound XV, 13fl-ethyl-17a-ethynyl-17fl-hydroxy-8-isogon-5 (10)-en-3-one XV.

7 Referring to FIGURE 7, an alternate route for the preparation of the gon-5(10)-ene XV startsfrom the gona-2,5 (10)-diene XII through an initial reaction with ethylene glycol in refluxing benzene in the presence of toluene p-sulfonic acidas catalyst to give the ketal 13pethyl 3,3 ethylenedioxy 8 isogon-5(10)-en-17fl-ol (XXII), which on oxidation of the 17-hydroxyl group with chromium trioxide in pyridine, gives l3p-ethyl-3,3,- ethylenedioxy-S-isogon-S 10)-,en-17-one (XXII) Ethynylation at the 17-position with lithium acetylide-ethylenediamine complex in dimethylacetamideconverts com pound XXII to 13/8-ethyl-3,3-ethylenedioxy-17a-ethynyl- 8-isogon-,5(10)-en-l7fl-ol (XXIII), which, by mild acid hydrolysis, affords the l3fi-ethyl-l7a-ethynyl-8-isogon- 5(10)-en-l7,3-0l XV. j

Referring to FIGURE 8 the compound XVIII, serves 17fi-ol XXIV, which, on reduction with lithium and an alcohol in liquid ammonia (Birch reduction), gives 13,8,- 17 diethyl 3-methoxy8-isogona-2,5(10)-dien-17p-ol (XXV).

Hydrolysis of compound XXV with mineral acid gives a mixture of the '136, Not-diethyl-17B-hydroxy-8-isogon- 5(lO)-en-3-one (XXVI) and 13fil7dt-diethyl-l7p-hydroxy-8-isogon-4en 3-one (XXVII). 1

While the hereinbefore described processes produce novel and'steroidal-like compounds which have an unnatural substituent at the Iii-position, it is apparent that the novel and valuable processes of the invention otter a unique feasible route to the 8-isomers of the correspond- ,ing natural steroids if the'nucleophilic compound used in the Michael condensation step is 2 -methyl-1,3-cyclopentanedione.

The aromatic ring of the phenylpropanol (FIGURE 1, I) used as the starting material for the preparation of the compositions and initial preparations of the invention may have one or more substituents, provided, however least one position ortho to the position of propanol-chain attachment is unsubstituted so that cyclodehydration to form a cyclic structure can eventually be effectuated. To activate such ortho position of said subsequent ring closure, an ortho-para-directing group (referring to electrophilic aromatic substitution) such as hydroxy, acyloxy, alkoxy, amino, alkylamino or acylamino is a necessary substituent on the aromatic ring. The term para-directing group (referring to electrophilic aromatic substitution) as used herein means an activating group such as those hereinbefore listed and which activate all positions on the aromatic nucleus. Thus, if the group is paradirecting, as defined above, it can be in a position meta to the ortho position to which ring closure is limited by steric considerations, said position'being activated even though another position ismore highly activated. Ring closure would not occur at the said more highly activated position because of the above mentioned steric limitations. The group may be present initially or may be introduced later but before ring closure, either directly, or by con version from a meta-directing group such as nitro. After the tetracyclic structure has been formed, substituents can be introduced into the aromatic A-ring which are not limited as above; however, if such substituted compound is to undergo a reduction, the group is preferably one not sensitive to reduction. After the A-ring has been reduced, the substituents on said A-ring may be the same as those originally present, or substituents to which'they starting propanol '-(I-)'is attached can be substituted, as,

for example, with an alkyl group,-such as methyl or ethyl.

:Moreover, this atom, to whichthe'phenyl' group is attached in Compound I, need not necessarily be carbon. It can be a hetero atom which would not interfere with subsequent catalytic" reductions, as, for example, oxygen or nitrogen. This 6-position, and it will be apparent, may be,

as in the case of the nitrogen, substituted with hydrogen or analkyl group. I

- The l-position carbon atom of the starting phenyl propanol (I) can also *be substituted, as, for example, with an 'alkyl'group,-such as methyl'and ethyl, and, as such, be. unchanged throughout the subsequent synthesis.

'6 In the tetracyclic structures of the invention this carbon atom will appear in the 7-position. For the processes of the invention and except for the limitations expressed in this specification, variations of the B-ring on the fully formed tetracyclic structures, or

on the intermediate leading thereto, are full equivalents of each other.

In the Michael reaction step, the 3-keto' substrate compound can be a 6-phenyl-1-hexen-3-one, or alternatively, a 6-phenyl-3-hexanone having attached to the 1-position a group which will eliminate with hydrogen to forma 6-phenyl-1-hexen-3-one under Michael conditions. Thus, a 3-keto compound with a l-dialkylamino substituent or its quaternary salt, a l-halo substituent, or a l-hydroxy substituent will react with the nucleophilic compound to form the Michael product. The nucleophilic compound can be a carbocyclic-1,3-dione of varying ring size, as for example a five-membered ring, a six-membered ring, etc., ultimately forming a corresponding five-membered, a six-membered, etc., D-ring in the tetracyclicstructure. The 1,3-cyclodione may also contain a hetero atom at positions other than position 2, thereby to provide a heterocyclic D-ring in the tetracyclic structure. Acylic nucleophilic compounds can be used in conducting the Michael reaction step and the open-chain of the resulting product thereafter ring-closed to form a cyclic D-ring.

For the processes of the invention, and except for the limitations expressed in this specification, variations of the D-ring on the fully formed tetracyclic structure, or on the intermediates leading thereto, are full equivalents of each other. By varying the group at the 2-position of the nucleophilic Michael condensation reactant, the invention provides a way to produce compounds resembling the 8-isomers of the natural steroids save at the 13-position. The starting materials for the preparation of the 2-substituted 1,3-cyclopentanediones are ketones of the structure RCH COCH where R is the substituent which will appear at the 2-position of the 1,3-cyclopentanediones. The starting ketone is reacted with diethyl oxalate in the presence of base to form a cyclopentane-1,3,4- trione-S-glyoxylic ester substituted at position 2 with the group R present in the starting ketone. The product is treated with acid to remove the S-substituent, and the 4-ketone function is then removed by Wolif-Kishner. reduction, involving selective semicarbazone formation at C and heating the product with base such as sodium hydroxide. On acidification the required 2-substituted-l, 3-cyclopentane dione can be isolated. Thus, the group R, which eventually forms the 2-substituent of the 1,3-cyclo pentane dione, can be any organic group which isstable to acid, and to Wollt-Kishner conditions and can be methyl, ethyl, propyl, cetyl, dimethylaminoethyl, etc. Thus, by varying the substituent at the 2-position of the 1,3 -cyclopentanedione, alkyl groups of varying chain length such as, for example, ethyl, isopropyl, cetyl, etc., may be introduced to form the 8,-isogonane correspondingly substituted at the Iii-position. Further 8-isogonanes may be prepared wherein the 13-position is substituted with any organic radical. Thus, but without limiting the generality of the foregoing, an aralkyl, cycloalkylalkyl, or a polycarbon-alkylene bridge bearing a hydroxy-, amino, or alkylamino-substituent can readily be placed in the 13-position, and from such compounds other variations of the 13-position substituent can be prepared, as haloalkyls from hydroxyalkyls, or quaternary salts, amides, alkenyls, etc. from aminoalkyls.

For the processes of the invention and except for the limitations expressed in this specification, variations at the 13-position of the fully formed tetracyclic structures or on the intermediates leading thereto are the fully equivalents of the claimed 13-position polycarbon-alkyl substituents, having physiological activity of the same type. In any of the intermediate structures or in the tetracyclic structures of the invention having either an aromatic, partially reduced, or totally reduced A-ring wherein the 17-position,'or position corresponding thereto in the 8-isogonane nucleus, is carbonyl, the carbonyl group can be convcrtedto a group such as hydroxymethylene by lithium aluminum hydride reduction (e.g. FIGURE 2) to acyloxymethylene by esterification of the hydroxymethylene group so formed; to alkoxymethylene by etherification of the hydroxymethylene group; to alkylhydroxymethylene by addition of the appropriate organometallic reagent to the carbonyl; or to alkynylhydroxymethylene by addition of the appropriate alkali metal 'acetylide in a suitable inert solvent (e.g. FIGURE 4); .all in the known manners. The carbonyl group may also to corresponding others or esters by methods known to those skilled in the art. The esters formed may be those of organic acids such as acetic acid, and an inorganic acid such as phosphoric or sulphuric. Also in any of the same intermediate or tetracyclic structures, the functional groups already present may be exploited, by procedures standard in the art, for the introduction of substituent groups such as hydroxyl, alkyl, and halogen, into ring-A and at the 6-, 7- and l6-positions, or positions corresponding thereto in the gonane nucleus. Such substituted derivatives are the full equivalents of the claimed corresponding parent compounds and of each other.

The specific reactions involved in the processes of the invention will now be considered, as follows, reference being made to the drawings for typifying compounds:

The vinyl ketones (VI) of'the invention are prepared by elimination of dialkylamine from the corresponding dialkylaminoethyl aminoketones (V), obtained by hydration of the acetylenic linkage in an acetylenic amine (IV). The acetylenic amines (IV) can be themselves prepared by a Mannich reaction from the corresponding acetylene (III) with-formaldehyde and a dialkylamine. The hydration can be carried out, for example, in aqueous sulfuric acid with mercuric sulfate as a catalyst. The corresponding quaternary salts, which may also be used in the subsequent Michael condensation, can be obtained by quaternization of the corresponding acetylenic dialkylaminoethyl amine, followed by hydration, or by quaternization of the ketoamine. The vinyl ketones can be prepared from these derivatives by the above elimination reaction. Thus the ketoamine or its quaternary salt can be treated with a base for this purpose, for example, with sodium hydroxide or a sodium alkoxide.

The vinyl ketones (VI) and dialkylamino ketones (V) are condensed with a nucleophilic compound under Michael reaction conditions. Thus the condensation can be carried out by bringing the two reagents together in solution in the presence of a base, for example, pyridine, triethylamine, diethylamine, sodium hydroxide, or sodium methoxide, and heating as required. The nature and amount of base employed in the condensation reaction will depend upon the particular reagents used. Where the vinyl ketone derivative employed is a keto-amine and dialkylamine is eliminated in the reaction, no added base may be required. Where the compound is a 2-alkylcyclopentane-1,3-dione (VII), the compound to be condensed with it is preferably a vinyl ketone, and the dione is used in excess of the molecular equivalent quantity. Suitable solvents are hydrocarbons, such as benzene, and anhydrous alcohols, such as methanol. If the reaction is carried out in benzene under refluxing conditions, water formed in the condensation may be azeotroped out of the reaction mixture with a Dean-Stark type trap.

The double cyclodehydration is brought about by dissolving a compound typified by Compound VIII in benzene containing a catalytic amount of p-toluene sulfonic acid and boiling the mixture under a Dean-Stark trap until two equivalents of water have been collected, or alternatively, by treating the same triketone with polyphosphoric acid at room temperature or slightly above until ring closure is complete. Catalytic hydrogenation of the gona-1,3,5(l0),8,14-pentaenes then gives a class of novel and useful 8-isomeric steroids. The starting pentaenes can have a 17-carbonyl (e.g. FIGURE 1) or be reduced to hydroxymethylene before hydrogenation (e.g. FIGURE 2). The catalytic hydrogenation can be carried out so that two molecular equivalents of hydrogen are absorbed, and the 8-isorneric product isolated directly (FIGURE 2), or the hydrogenation can be interrupted after one molecular equivalent of hydrogen has been absorbed and the intermediate gona-1,3,5(10),8-tetraene isolated and then further hydrogenated to an 8-isomeric steroid (FIG- URE 3). Solvents such as benzene, anhydrous ethanol, and methanol are suitable, and the hydrogenation is preferably carried out at room temperature and pressure.

While the tetracyclic compounds in this specification and the appended examples are named to describe the configuration to that of the natural steroids, it is to be understood that unless otherwise indicated, the product of each of the given manipulative procedures is a racemic mixture which contains said named compound and its enantiomorph.

Representative formulations embodying specific compositions of the invention are as follows.

A capsule for use as an oral hypocholesterolenic agent contains:

13/3 ethyl-3-methoxy-8-isogona-1,3,5(10)-trien- 17,8-ol 20100 Magnesium stear-ate 24 Lactose, U.S.P. q.s. ad 480 A tablet for use as an oral hypocholesterolenic agent contains:

ethyl-3-methoxy-8-isogona-1,3,5(10)-trien- -01 20-100 Magnesium stearate 0.65 Talc, U.S.P. 10.00 Avicel (American Viscose Division, FMC

corp). 115.00 Lactose, U.S.P. q.s. ad 260.00

A tablet for use as an agent for the control of postmenopausal syndrome contains:

13;? ethyl-3-methoxy-8-isogona-1,3,5(l0)-trien- Ph armaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet-disintegrating agents: it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided compound. In the tablets the compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets, preferably contain from 5 to 10 to 99% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low melting wax, and cocoa butter. The term preparation is intended to include the formulation of the compound with encapsulating material asv carrier providing a capsule in which the compound (with or without other carriers) is surrounded by carrier, which is 9 surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used for oral administration.

I Liquid form preparations include solutions, suspensions, and emulsions. The compounds are insoluble in water, but can be dissolved in aqueous-organic solvent mixtures that are non-toxic in the amounts used. As an example may be mentioned water-propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solutions. 'Aqueous suspension suitable for oral use can be made by dispensing the finely divided compound in water with viscous material, natural or synthetic gums, resins, etc.', for example, gum arabic, ion-exchange resins, met-hylcellulose, sodium carboxymethylcellulose and other well-known suspending agents,

Preferably the pharmaceutical preparation is in unit dosage form. In such form the preparation is sub-divided in unit doses containing appropriate quantities of the compound: the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted powders of vials or ampules. The unit dosage form can be a capsule, cachet, or a tablet itself, or it can be the appropriate number of any of these in packaged form. The quantity of compound in a unit dose of preparation may be varied or adjusted from 1 mg. to 100 mg. (generally within the range of 2.5 to 25 mg).

The claim'ed compositions having physiological activity can be incorporated into pharmaceutical formulations including sustained-release agents.

The following preparations illustrate the manner of making the chemical compounds which are the starting materials for use in the processes of the invention.

Preparation 1: 3 (3 methoxyphenyD-n-propyl bromide.Cool 3-(3-methoxyphenyl)propan-l-ol 125 g.) in benzene (200 cc.) to and add a solution of phosphorus tribromide (8 6 g.) in benzene (150 cc.) dropwise so that the temperature of the mixture does not rise above Keep the mixture at 0 for 1 hr. and then heat at 60 for 3 hrs. Cool, pour onto ice, dilute with ether and separate the organic layer. Wash the organic solution with 3 N aqueous sodium hydroxide, water and dry. Remove the solvent and distill the residue to obtain the title compound (131 g.) B.P. 146-148/17 mm. 11,, 1.5497.

C H BrO calculated: C, 52.4; H, 5.7; Br, 34.8. Found: C, 54.4; H, 5.7; Br, 34.7.

Preparation 2: 5m-methoxyphenylpent-1-yne.--Add 3- (3-methoxyphenyl)- n-propyl bromide (14 g.) in tetrahydrofuran (l5 cc.) with rapid stirring to a solution of sodium acetylide (from 1.84 g. sodium) in liquid ammonia (125 cc.) in a Dewar flask. Continue stirring for 22 hours, then add ammonium chloride (3 g.) and water (50 cc.) Collect the product with ether and wash and dry the ethereal solution. Distillto obtain 5-rn-methoxyphenylpeut-lyne (7.1 gr., 66%), B.P. 75-'78 C./0.06-

C H O calculated: C, 82.7%; H, 8.1%. Found: C, 82.2%;H,7.8%. v

Preparation 3: 1-diethylamino-6-m-methoxyphenylhex- 2-yne.Allow S-m-methoxyphenylpent-l-yne (8 g.) to stand for 12 hours at 70 C. under nitrogen with water (2.5 cc.).trioxan (0.5 g.), 30% formalin(5.5 g.), diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.)

and cuprous chloride (0.13 g.). Make the. cooled solu tion alkaline with 10% aqueous sodium hydroxide and extract with ether;jthen extract the ether extract with 10% hydrochloric acidrwash the acid extract with ether, make alkalinewith 10% aqueous sodium hydroxide, extract with ether, and then wash and dry the ether extract.- Distill to obtain l-diethylamino-6rm methoxyphenylhex- 2 -yne (10.6, g., 88%), B.P. 130 131.c./o.1 mm.

, C H N calculated: C, 78.7%; H, 9.7%. Found: C, 78.9%; H, 9.6%. Y

Preparation 4: l-diethylamino-6-m-methoxyphenylhexan-3-one and 6-m-methoxyphenylhex-1-en-3-one.-Add mercuricsulphate, (.0.45 g.),to a swirled solution of l-di 10 ethylamino-6-m-methoxyphenylhex-2-yne (8.5 g.) in concentrated sulphuric acid (2.5 cc.) and water (25 cc.). Keep the solution under nitrogen at C. for 1 hour,

then cool, make basic with 10% aqueous sodium hydroxide, and filter through glass wool to remove mercuric oxide. Extract product with ether and wash and dry the ethereal solution. Remove the solvent to obtain the crude ketoamine 1-diethylamino-G-m-methoxyphenylhexan-3-one, infrared absorption peak at 1710 ,u. Distill under reduced pressure with partial elimination of diethylamine, to obtain a mixture of the ketoarnine l-diethyl amino-6-m-methoxyphenylhexan-3-0ne and the vinyl ketone 6-m-methoxyphenylhex-1-en-3-one (7.1 g., ca. 76% B.P. -145 C./0.1 mm.; infrared absorption peaks at 5 .85 and 5.95 the ketoamine predominating.

Distill a second portion of the crude ketoamine 1-di-- ethylamino-6-m-methoxyphenylhexan-3-one very slowly over a period of 30 minutes through a Vigreux fractionating column 10 cm. high and 1 in. diameter under reduced pressure to eliminate most of the diethylamine. Dissolve the 6-m-methoxyphenylhex-1-en-3-one obtained (B.P. 114 C./0.7 mm.) in ether and wash the ether solution with dilute hydrochloric acid, followed by aqueous sodium bicarbonate and water. Dry and evaporate. Distill the residue to give the pure vinyl ketone as a colorless liquid, B.P. 76 C./O.3 mm.

C H O calculated: C, 76.4%; H, 7.9%. Found: C, 76.3%; H, 8.0%.

Mix a third portion of the crude undistilled l-diethylamino-6-m-methoxyphenylhexan-3-one (3 g.) with methyl iodide (3 g.). An exothermic reaction soon develops.

After 12 hours wash the mixture with ether to remove unchanged reactants and subject to reduced pressure (15 min.) -to remove ether remaining: the residue is the crude methiodide of the ketoamine (4.6 g.).

Infrared absorption peaks at 5.85

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

' potassium hydroxide (34 g.) in dry ethylene glycol at 130, and heat the mixture .to for 1 hour, followed by 30 minutes at Distill the glycol at 0.01 mm., dissolve the residual solid in water (150 cc.) and make the solution acid to Congo Red with hydrochloric acid. Cool to 0 overnight and filter. Recrystallize the residue from water to obtain 2-ethylcylopentane-1,3-dione (10 g. M.P. 180 with sublimation.

This compound is useful for preparing the novel compositions of this invention which have hormonal activity.

Preparation 6 2- 6-m-methoxyphenyl-3 -oxohexyl -2- ethylcyclopentane-l,3-dione.Reflux a mixture (5.25 g.) of 1-diethylamino-6-m-methoxyphenylhexan-3-one and 6-m-methoxyphenylhex-1-en-3-one with 2-ethylcyclopentane-l,3-dione (3.3 g.) in dry 0.12% methanolic solution of potassium hydroxide for 18 hours. Filter the resulting solution, evaporate to dryness and dissolve the residue in ether. Wash the ether solution with alkali, hydrochloric acid, and water, dry and evaporate to obtain as residue the triketone 2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclopentane-L3-dione (7.1 g.) as a gum.

This compound is useful as an intermediate for the preparation of the novel compositions of this invention which have hormonal activity.

Preparation 7: 13B-ethyl-3-methoxygona-l,3,5(10),8,14- pentaen-17-one.Refiux the triketone 2-ethyl-2-(6-mmethoxyphenyl-3-oxohexyl cyclopentanel,3-dione g.), in benzene (150 cc.) and toluene-p-sulphonic acid (2 g.) until the theoretical amount of water (0.72 cc.) for double cyclodehydration has been collected in a Dean- Stark separator. Wash the cooled reaction mixture after removal of solvent under reduced pressure, B.P. ca. 220/ 0.01 mm., to obtain an almost colorless glass (5.7 g.). Crystallize the glass from methanol containing a little ethyl acetate to obtain pure l3B-ethyl-3-methoxygonal,3,5(10),8,14-pentaen-17-one (3.7 g.), M.P. 77-80; ultraviolet absorption peak at 311 mu (e 28,000).

C H O calculated: C, 81.6%; H, 7.5%. Found: C, 81.3%; H, 7.3%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

The following examples illustrate the manner of using the claimed processes of the invention for the preparation of the claimed compositions of the invention, and for the preparation of natural steroids.

Example l.13(3-methyl-3-methoxy-8-iso-gona- 1,3,5 10)-trien-17-one Hydrogenate 13B methyl 3 methoxy gona- 1,3,5(l),8,l4 pentaen 17 one (3 g.) dissolved in ethanol (150 cc.) at atmospheric pressure in the presence of a 4% palladium on barium sulphate catalyst (3 g.) until hydrogen uptake ceases. Filter the catalyst and evaporate the filtrate to obtain residue and crystallize from ethanol to obtain the title compound (1.1 g.).

This compound has estrogenic activity, lowers the lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 2.-13B-methyl-3-methoxy-8-iso-gona- 1,3,5 10)-trien-17-one Dissolve 13B methyl 3 methoxy gona 1,3, 5(10),8,14 pentaen l7 one (1 g.) in benzene (35 cc.) and shake with hydrogen at atmospheric pressure in the presence of a palladium on charcoal catalyst (0.5 g.) until hydrogen uptake ceases. Remove the catalyst, evaporate the solvent and recrystallize the residue from ethanol to obtain the title compound (0.55 g., 54%), M.P. 151-3.

This compound has estragenic activity, lowers the lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

To obtain 13 3 ethyl 3 methoxy 8 isogonal,3,5(l0) trien 17 one, hydrogenate 13B ethyl 3- rnethoxygona 1,3,5(l0),8,14 pentaene l7 one according to the manipulative procedure described above.

To obtain 13 3 isopropyl 3 methoxy 8 isogona- 1,3,5 (10) trien 17 one, hydrogen-ate 13 8 isopropyl- 3 methoxygona 1,3,5(10),8,14 pentaen 17 one according to the manipulative procedure described above.

These compounds have estrogenic activity, lower the blood lipid level, and are useful as intermediates in the preparation of the hormonal compounds of this invention.

Example 3.13fi-ethyl-3-methoxy-8-isogonal,3,5(l0)-trien-l7-one Shake 13 3 ethyl 3 methoxygona 1,3,5(10),8--

Example 4.13 3-ethyl-3-methoxy-17,17-ethylenedioxy 8-isogona-l,3,5(10)-triene Shake 1313 ethyl 3 methoxy 17,17 ethylene- 12 dioxy gona 1,3,5(10),8,14 pentaene (0.7g.) in eth-v anol (50 cc.) with hydrogen at atmospheric pressure in the presence of a 10% palladium ofcharcoal catalyst untilg2 molecular equivalents of. hydrogenhave been absorbed. Crystallize the residue obtained after removal of catalyst and solvent from a mixture-of methanol (25 cc.) and ethanol (25 cc.) to obtain the title compound (0.35 g.), M.P. 131-3".

C H O calculated: C, 77.1%; H, 8.8%. Found: C, 77.2%; H, 3.8%.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 5 .13,8-ethyl-3-methoxy-8-isogona-1,3,5 10)- trien-17-one Pass hydrogen chloride through a solution of 13,3-

ethyl 3 methoxy 17,17 ethylenedioxy 8 isogonal,3,5(l0) triene (0.2 g.) in chloroform (5 cc.) at room temperature for 1 hour. Wash the product to remove hydrogen chloride, dry, and evaporate the solvent to obtain an oil and crystallize from ethanol toobtain the title compound (0.07 g.), M.P. -2, undepressed on admixture with a sample otherwise obtained.

This compound has estrogenicactivity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 6.13p-n-propyl-3-methoxy-8-isogona- 1,3,5 (10)-trien-17-one Hydrogenate 13,8 n propyl 3 methoxygona 1,3, 5(l0),8,14 pentaen l7 one (5 g.) in ethanol (500 cc.) over 10% palladized charcoal (2 g.) until two molar equivalents of hydrogen. have been absorbed. Filter the catalyst, evaporate the solvent and recrystallize the residue from ethanol to obtain the title compound.(2.8 g.), M.P. 133-134"; ultraviolet absorption peak at 280 m (e 2,300) 287 m (6 2,300); infrared absorption peak at 5.76 ,u..

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 7.-1313-isobutyl-3-methoxy-8-isogona-' 1,3,5 ('10)-trien-17-one C H O calculated: C, 80.9%; H, 9.2%. Found: C,

To obtain 13 3 n butyl 3 methoxy 8 isogona- 1,3,5 10) trien 17 one, hydrogenate 13,8 n butyl- 3 methoxygona 1,3,5(10),8,14 pentaen 17 one according to the manipulative procedure described above.

T o obtain 135,6 dimethyl 3 methoxy 8 isogona- 1,3,5 l0) trien 17 one, hydrogenate 13/3,6-dimethyl- 3 methoxygona 1,3,5(10),8,14 pentaen 17 one' according to the manipulative proceduredescrib ed above.

To obtain 135,7 dimethyl 3 methoxy 8 isogona- 1,3,5 (10) trien 17 one, hydrogenate 135,7 dimethyl- 3 methoxygona -1,3,5(10),8,14 pentaen I7 one according to the manipulative procedures described above.

To obtain 13B 'n' propyl 3 hydroxy 8- isogona l,3,5(l0) 7 trien 17 one, hydrogenate 13 3- n prop'yl 3 hydroxygona 1,3,5(I0),8,14 pentaen- 17 one according to the manipulative procedure described above.

' To obtain 13/8 n butyl 3 hydroxy 8 isogonal,3,5(l0) -.trien 17 one, hydrogenate 1313 -'n butyl- 13 i 3 hydroxygona 1,3,5(10),8,'14 pentaen- 17 one according tothe manipulativeprocedure described above.

To obtain 1 3pethyl 2,3 dimethoxy- 8 isogona- '1,=3,5(l0)-' trien 17 one, hydrogenate 13 3 ethyl- '2,3"- dimethoxygona- 1,3,5(10)',8,14 -'pentaen -'17-one according to the manipulative procedure described above. 1 l

II- To lob'tain 13,9 ethyl 1,3-dimethoxy- 8-isogona-1,3, 5( 10)-trien-17-one, 'hydrogenate 13fl-ethyl-L3-dimethoxygona-l,3,5(10),8;l4-pentaen-l7-one' according to the manipulative procedure described above.

To obtain 13 3-(3-hydroxypropyl)-3-methoxy-8-isogona- 1,3,5 (10)-trien-17-one, hydrogenate 13fi-( 3-hydroxypropyl)-3 -methoxygona-fl,3,5(10),8,14-pentaen-l7 one according to the manipulative procedure described above.

To obtain 13,3 isobutyl- 3 pentyloxy-8-isogona-1,3, 5 10)-trien-l7-one, hydrogenate l3B-is'obutyl-3-pentyloxy- 'g'ona-1,3,5(10),8,14-pentaen-17-one according to the manipulative procedure described above. To obtain 13 3-(3-hydroxypropyl)-3-cyclopentyloxy-8- isogona-l,3,5(l)-trien-17 one, hydrogenate 13 3-(3-hydroxypropyl)-3-cyclopentyloxygona-1,3,5 (10) ,8,14 pentaen-17-one according to the manipulative procedure described above.

To obtain 13/3 phenethyl 3 hydroxy-8-isogona-1,3, )-trien-17-one, hydrogenate l3fi-phenethyl-3-hydroxygona-1,3,5(10),8,14-pentaen 17 one according to the manipulative procedure describe above.

To obtain 13fl-(2-diethylaminoethyl)-2,3-dimethoxy-8- isogona-1,3,5(l0)-trien-l7-one, hydrogenate 13B-(2-didiethylaminoethyl)-2,3 dimethoxygona 1,3,5 (10),8,14- pentaen-l7-one according to the manipulative procedure described above.

To obtain 13,8-(3 dirnethyl-aminopropyl)-6-methyl-1,3-

dim'ethoxy-8-isogona-1,3,5'( 10) -trien-17-on'e, hydrogenate 135-(3-dimethylaminopropyl)-6-methyl 1,3 dimethoxy- =gona-1',3,5(10),8,14-pentaen-17-one according to the manipulative procedure described above.

T To obtain 13,8-n butyl-1,3-diethoxy-6-ethyl-8-isogona- 1,3,5 (10)"-trien-1-7-one,' hydrogenate 13;3-n butyl1,3-diethoxy-6-ethylgona-1,3,5'(10),8,14-pentaeh 17 one according'to the manipulative procedure described'above.

: To obtain 1-3/3-n-propyl-2-ethoxy-3-inethoxy-8-isogona- 1,3,5 (10)-trien-17-one, hydrogenate 13,3-n-propyl-2-ethoxy-2-ethoxy-3-methoxygona-1,3,5(10),8,14-pentaen 17- one according to the manipulative procedure described above, Q

These compounds have e'strogenic activity, lower the blood lipid level,"and*are useful as intermediates in the preparation of the hormonal" compounds of this invention."

- Example; 8. .-13fl-cetyl-3-methoxy-8-isogonai 1,3,5 10)-.trien-17.-one 1 0 Shake 4 13,3 7 cetyl 3- methoxygona -l,3,5(10),8,14 pentaen-3-one (1.9 g.) in ethanol (250 cc.)*with hydrogen atatmospheric pressure in the presence of a 10% palladium on charcoal catalyst-(1 g.) until uptake of hydrogen ceases. Remove the catalyst and evaporate to obtain a colorless oil, and distill at 245 55 (bath temperature) 0.0002 mum, to obtain the title-compound; ultraviolet absorption peak at.280 mp. (e 1,560).

C H O calculated: C, 82.5%; H, 11.0%, Found: C, 82- p y i jThifs compound has estrogenic activity,;lowers the blood lipidflevehand is useful as an; intermediate for preparing the hormonal compounds", of this invention.

3 l,3, (10)'-trien-l7-one- Y Hydrogenate 13B methyl-3-hydroxygona-l,3,5(10),8, "14-pentaen 17-one (Q-lo g.) in ethanol (2 0 cc.) at atmospheric'pressure in the presence of a 30% palladizedcha-rcoal catalyst (0.075 g.). When 2.2 molar equivalents of hydrogen have been absorbed, (4"hours filter the catalyst and evaporate the filtrate. Recrystallize the residue from methanol to obtain the title compound as colorless plates, M.P. 246-9 with-sublimation; ultraviolet absorption peak at 281 mp. (e 2,150).

This compound has estrogenic activity, lower the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

, Example 10.-+l3,3-methyl-3-hydroxy 8-isogonal,3,5(10)-trien-17-one Hydrogenate 13B methyl3-hydroxygona-l,3,5(10),8, 14-pentaen-17-one (0.14 g.) in a mixture of benzene (37.5 cc.) andtetrahydrofuran (12.5 cc.) --at atmospheric pressure using a 10% palladium on charcoal catalyst (0.075 g.) until hydrogen uptake is complete (6 hours). Remove the catalyst and the solvent to obtain a residue and crystallize from methanol to obtain the title compound, M.P. 246-7.5; ultraviolet absorption peak at 281 mu (e 1,900), confirming complete hydrogenation of the ethylenic bonds.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 1 1.--13B-methyl-3-hydroxy-8-isogona- 1,3,5 l0) -trien-17-one Hydrogenate 13p methyl 3-acetoxygonal-1,3,(10),8, 14-pentaen-17-one (0.38 g., obtained by the acetylation of bisdehydroestrone with pyridine and acetic anhydride) in ethanol (20 cc.) at atmospheric pressure with a 10% palladium on charcoal catalyst (0.02 g.) until hydrogenation ceases. Filter the catalyst and evaporate the solvent to obtain colorless crystals of 13B-methyl-3-acetoxy-8-isogona-1,3,5(10)-trien-l7-one. Take up the product in methanol (3 cc.), and add 3 N sodium hydroxide solution (1 cc.). After 15 minutes, acidity the solution and filter the precipitate obtained, and recrystallize from methanol to obtain the title compound, M.P. 253-5 with previous sublimation and softening at 247; ultraviolet absorption peak at 281 m (6 2,200).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

.and absorb on a column of ion exchange resin (prepared by mixing asynthetic hydrated acid magnesium silicate and celite resin in the proportion 4:1 by weight, and then washing with hydrochloric acid and water and drying at Elute the absorbed material with benzene to remove a by-product, and subsequently elute with ether to obtain the title compound (0.22 g.), M.P. -82 after recrystallization from methanol; infrared absorption peak at 3.01, 5.34,u..

. This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 13.1 3fi-ethyl-3-hydroxy-8-isogona-1,3,5 l0 trien-17-one Hydrogenate 13B-ethyl-3-hydroxygona-1,3,5 10 ,8, 14- pentaen-l7-one (0.4 g.) in ethanol (25 cc.) at atmospheric pressure using a 10% palladized charcoal catalyst (0.2 g.) until 2.2 molar equivalents of hydrogen are taken up (3 hours); filter and evaporate to obtain a crude product and recrystallize from methanol to obtain colorless crystals of the title compound (0.215 g.), M.P. l89-l93 C. with sublimation to needles, M.P. 205-206 C. Further recrystallization of the material of M.P. 189-193" C. raises its melting point to 191-193 C.; ultraviolet absorption peak a t 280.5 my. 62,280

1 5 C H O Calculated: C, 80.25%; H, 8.5%. Found: C, 80.2%; H, 8.4%.

This compound has estrogenic and blood lipid lowering activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 14.13;8-methyl-3-methoxy 8 isogona-1,3,5-

() -trien-1 7 3-01 Shake I 13/3-methyl 3 methoxygona-1,3,5(10), 8,14- pentaen-17fl-ol (2.3 g.) in ethanol (100 cc.) with hydrogen at atmospheric pressure in the presence of a 10% palladium on charcoal catalyst (1.2 g.). Remove the catalyst and solvent and crystallize the residue from methanol and then from a mixture of benzene and light petroleum to obtain the title compound, M.P. 103104 C. on admixture with authentic material obtained by another route, M.P. 101-102" C.

This compound has estrogenic and blood lipid lowering activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 15.-l3p-ethyl-3-methoxy-8-isogona-l,3,5(l0)- trien-17,8-o1

Shake 13;? ethyl 3 methoxygona 1,3,5(10),8,14- pentaen-17B-ol (3.4 g.) in ethanol (150 cc.) with hydrogen at atmospheric pressure in the presence of a 10% palladium on charcoal catalyst (3.4 g.). Remove the catalyts and solvent and crystallize the product from a mixture of ether and light petroleum to obtain the title product, M.P. 130-131 C.

C H O Calculated: C, 79.9%; H, 9.4%. Found: C, 79.9%; H, 9.2%.

This compound has estrogenic and blood lipid lowering activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 1 6.-1 3 B-n-propyl-3-methoxy-8-isogona- 1,3,5 (10) -trien-1713-ol Add sodium borohydride (2 g.) to 13,6-n-propyl-3- methoxy-8-isogonal-1,3,5(10)-trien-17-one (3 g.) in ethanol (100 cc.), and reflux the mixture for one hour. On cooling, work up the product in the usual manner and recrystallize from ethanol-water (9: 1) to obtain the title compound (2.1 g.) M.P. 116-190 C. The analytical sample obtained by a further recrystallization from etherhexane has M.P. 120-121 C.; infrared absorption peak at 2.89 no absorption in 5.71-5.88 region.

C H O Calculated: C, 80.2%; H, 9.6%. Found: C, 80.3%; H, 9.6%.

This compound has estrogenic and blood lipid lowering activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 17.13/3-isopropyl-3-methoxy-8-isogona-1,3,5-

(10) -trien- 176-01 Add 13fi-isopropyl 3 methoxy-8-isogona-1,3,5(l0)- trien-17fi-one (1 g.) to sodium borohydride (0.5 g.) in methanol (100 cc.). Stir the mixture for 1 hour at 50 (bath temperature), and on cooling acidify with aqueous acetic acid and pour into brine. Extract the product with ether and Work up in the usual manner to obtain a crys talline residue. Recrystallize from methanol and then from acetonitrile-water to obtain the title product (500 mg.), M.P. (after drying for 5 hours over phosphorus pentoxide at 0.05 mm.) 64-69".

Infrared absorption peaks at 2.96, 6.21, 7.97 t; no absorption in 5.71-5.88 1. region.

This compound has estrogenic activity, lowers the lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 18.-13/8-isobutyl-3-methoxy-8-isogona- 1,3,5(10)-trien-17B-ol Add sodium borohydride (7 g.) to 13p isobutyl 3- methoxy 8 isogona 1,3,5(10) trien 17 one (2 g.)

in ethanol (80 cc.) and reflux the mixture for 1 hour. On

cooling, acidity the mixture with aqueous acetic acid and evaporate 'to dryness under reduced pressure. 'Add water and-collect the product with ether. Recrystallize from methanol and then from ether-hexane to obtain the title product (2 g.), M.P. 137; ultraviolet absorption peaks at 280 III/L (62,000), 287 m (61,900); infrared absorption peak at 288 no absorption in 5.71-5.88 1. region. C H O Calculated: 'C, 80.4%; H, 9.8%. Found: C, 80.4%;H, 9.7%. t I i y This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 19.13fi-ethyl-8-isogona-1,3,5(10)- trien-3, l7/3-diol Keep 13B ethyl 3 hydroxy 8 isogona 1,3,5(10)- trien-17-one (1.04 g.) for 3 hours at room temperature in methanol (50 cc.) containing sodium borohydride (1 g.). Acidify the mixture with acetic acid and concentrate to a thick slurry. Add water and collect the product with ether. Work up in the usual manner to obtain residue and twice recrystallize from methanol to obtain the title product (64 g.) M.P. 1895-1925"; ultraviolet peak at 280 mp. (e2,000); infrared absorption peaks at 2.99, 3.08u.

0 9112 02 Calculated: C, H, 9.15%- Found: C, 79.4%; H, 9.30%. I

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 20.13B-methyl-3,17,3-dimethoxy-8- isogona-1,3,5 10) -triene Add 13,8 methyl 3 methoxy 8 isogona 1,3,5(10)- trien-17p-o1 g.) in methylene chloride (50 cc.) containing 1 drop of boron trifluoride ether-ate to diazomethane (from N-nitrosomethylurea, 2.05 g.) in methylene chloride (40 or.) Work up and recrystallize the product from ethyl acetate-hexane and then from methanol to obtain the title compound (3 g.), M.P. 106108.

C H O Calculated: C, 80.0%; H, 9.4%. Found: C, 79.8%; H, 9.3%.

This compound has estrogenic and blood lipid lowering activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 2l.13B-ethyl-3,17B-dimethoxy-8- isogona-1,3,5(10)-triene Add 1319 ethyl 3 methoxy 8 isogona 1,3,5(l0)- trien-17fl-ol in methylene chloride (25 cc.) to diazomethane as previously described. Crystallize the product from hexane, dissolve in hexane-benzene (4:1) and chromatograph on neutral alumina. Elute with benzene; crystallize from n-hexane to obtain the title compound, M.P. 113; ultraviolet absorption peaks at 279 mp (62,200), 288 m (e2,100).

C31H3oO2 Calculated; C, 9.1%. Found: C, 80.1%; H, 8.9%.

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing, the hormonal compounds of this invention.

Example 22.13B-n-propyl-3,17B-dimethoxy- 8-isogona-1,3,5(10)-triene Add excess diazomethane in ether (60 cc.) to 13,8- propyl 3 methoxy 8 isogona ,1,3,5(10) trien- -01 (1 g.) in methylene chloride (50 cc.) containing 1 drop of boron trifiuoride etherate. Filter the solution, wash with aqueous sodium hydroxide and then with water, and dry. Remove the solvent and chromatograph the residue in hexane-benzene (9:1) through a column of neutral alumina (50 g.). Crystallize from ethanol, then from hexane, to obtain the title compound (0.35 g.), M.P." 92.5-93.5; no infrared'absorption in the 2.86- 3.33,u region. p

C H O Calculated: C, 80.4%; H, 9.8%. Found: C, 80.5%; H,'10.1%.

1 7 This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 23.-13B-ethyl-3-methoxy-17 3-acetoxy- 8-isogona-l ,3,5 10) -triene Dissolve 135 ethyl 3 methoxy 8 isogona- 1,3,5 10)-trien-17fi-ol (1 g.) in pyridine (5 cc.) and acetic anhydride (5 cc.) and allow the mixture to stand at room temperature for 18 hours. Remove the solvent in vacuo and crystallize the residue to obtain the title compound; ultraviolet absorption peak at 286 my. (e2,000).

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 24.13,8-n-propyl-3-methoxy-17[3-acetoxy- 8-isogona- 1,3,5 10) -triene Prepare the starting material, 13B-propyl-3-methoxy- 8-iosgona-l,3,5(10)-trien-l7B-ol, by shaking 13 8-propyl- 3-methoxygona-l,3,5(10),8,14-pentaen-17-one (5 g.) in ethanol (100 cc.) containing 10% palladized charcoal (2 g.) until hydrogen uptake ceases. Obtain the product by filtration of the catalyst, evaporation of the solvent and crystallization from ethanol; then reflux with ethonal (100 cc.) and sodium borohydride (0.2 g.) for 30 minutes. Acidify the reaction mixture with acetic acid, evaporate almost to dryness, and water, and collect the product in ether. Wash, dry, and evaporate the ethereal solution and crystallize the residue from methanol. Dissolve this product (1 g.) in pyridine (5 cc.) and acetic anhydride (5 cc.) and allow to stand at room temperature for 18 hours. Remove the solvents and obtain the title compound by crystallizing from methanol; ultraviolet absorption peak at 286 m (61,900; 1,700).

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 25 .--1 3 B-n-propyl-3 -methoxy-17 8- benzoyloxy-S-isogona-1,3,5 10) -triene Prepare 13B-propyl 3 methoxy-8-isogona-l,3,5(l0)- tli6I1-17j3-Ol (1 g.) as described in the previous example. Treat with benzoyl chloride (1.5 cc.) in pyridine (10 cc.) and keep at room temperature for 18 hours. Add water, and take the product up in ether. Wash the ethereal solution with water, 10% aqueous potassium hydroxide, water, 10% hydrochloric acid, and dry with brine. Evaporate the solvent and crystallize from ethanol to obtain the title compound; ultraviolet absorption peak at 286 m (e 1,900).

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds ofthis invention.

To obtain 13B-thyl-3-methoxy-17,8-benzoyl0xy-8-isogona 1,3,5 (10)-triene, treat 13[i-et-hyl-B-methoxy-Sdsogona-1,3,5(10)-trien-l7B-ol with benzoyl chloride in pridine according to the manipulative procedure described above.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate in the preparation of the hormonal compounds of this invention.

Example 26.--13fi-methyl-3-methoxy-l7,17- propylenedioxy-8-isogona-1,3,5 10) -triene Shake IS S-methyl 3 methoxy-17,l7-propylenedioxygona-1,3,5(l0), 8,14-pentaene (1 g.) in ethanol (45 cc.) with 10% palladized charcoal (0.4 g.) in an atmosphere of hydrogen until uptake ceases (ca. 25 cc.). Remove solvent by filtration, evaporate the solvent under reduced pressure, and crystallize the residue from methanol to obtain the title compound; ultraviolet absorption peaks at 278, 286 mu (6,000; 1,800).

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 27.-l3fi-ethyl-3-methoxy-l7,17-(2,2- dimethylpropylene-dioxy) -8-isogona-1,3,5 (10) triene Shake l3fi-ethyl-3 methoxy-l7, l7-(2,2 dimethylpropylenedioxy)-gona-1,3,5(l0),8,14-pentaene (1 g.) in ethanol (75 cc.) containing 10% palladized charcoal (1 g.) in an atmosphere of hydrogen until uptake ceases. Remove the catalyst by filtration and evaporate. Crystallize the residue from ethanol to obtain the title compound, M.P. 173-8"; ultraviolet absorption peaks at 280, 287 m (2,500; 2,200).

C H O Calculated: C, 78.1%; H, 9.4%. Found: C, 77.8%; H, 9.2%.

This compound has estrogenic activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 28.-13p-ethyl-3-methoxy-17,17-

diethoxy-8-isogona-1,3,5 10)-triene Treat l3fl-ethyl-3-methoxy-8-isogona-l,3,5(10) trien- 17-one (1 g.) in ethanol (4 cc.) and ethyl ort-hoformate (1 cc.) with 1 drop of sulfuric acid, and heat for 30 minutes at 40. Add ethyl orthoformate (0.5 cc.) and heat at 55 for a further 30 minutes. Cool the solution and tip it into a saturated sodium bicarbonate solution, and take the product up in ether. Wash, dry, and evaporate the ethereal solution. Filter the residue in hexane-benzene (4: 1) through alumina (50 g.). Evaporate the solvent to obtain the title compound; ultraviolet absorption peaks at 278, 286 mg (e2,000, 1,800).

This compound has estrogenic and blood lipid lowering activity, and is useful as an intermediate for preparing the hormonal compounds of this invention.

To obtain 13p-n-propyl-3-methoxy-17,17-diethoxy-8- isogona-1,3,5(10)-triene, treat I3B-n-propyl-3-methoxy- 8-isogona-1,3,5(10)-trien-17-one with ethanol, ethyl orthoformate, and sulfuric acid according to the manipulative procedure described above.

This compound has an estrogenic and blood lipid lowering activity, and is useful as an intermediate in the preparation of the hormonal compounds of this invention.

Example 29.-1 3 fi-ethyl-3-methoxy-8-isogona- 2,5 10) -dien-17fl-ol Dissolve 13 ,8-ethyl-3-methoxy-8-isogona-l,3,5 (10)-trien- 1719-01 (1 g.) in l-methoxy-Z-propanol cc.) and ammonia (200 cc.). Add lithium (l g.) over 20 minutes, stir for 2 hours and allow the ammonia to evaporate. Add water (500 cc.), extract the reaction mixture with benzene and wash the organic solution with water and dry (MgSO Evaporate the solvent and crystallize the residue from methanol-ethanol to obtain the title product (800 mg.) M.P. -9 Recrystallize a sample from benzene-petroleum ether to obtain the pure compound M.P. 112.5113. Infrared spectra: 2.87, 5.8, 6.0 Found: C, 79.35; H, 9.75 C H O requires: C, 79.42; H, 9.99.

This compound is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 30.13,6-ethyl-17,3 hydroxy-S-isogona 5( 10)-en-3-one Dissolve 13,8-ethyl-3-methoxy 8 isogona-2,5(l0)-dien- 1718-01 (1 g) in ethanol (75 cc.). Add a solution of oxalic acid (1.15 g.) in water (21 cc.) and allow to stand for 45 minutes. Dilute the reaction mixture with water and extract with ether. Wash the ethereal solution with aqueous sodium hydrogen carbonate, brine and dry and evaporate to obtain the title compound as a gum (0.9 g.).

Infrared spectrum: 2.95, 585g. Found: C, 79.12; H, 9.8; C H O requires: C, 79.12; H, 9.78.

This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

19 Example 3 1. 13fl-ethyl-17 8-hydroxy-8-isogon-5 10) -en- 3-one and 13,9-ethyl-l7p-hydroxy-8-isogon-4-en-3-one Dissolve 13 3 ethyl-3-methoxy-8-isogona-2,5(10)-dien- 17fi-ol (0.5 g.) in ethanol (25 cc.) and methanol (25 cc.). Add 3 N hydrochloric acid (30 cc.) and allow the mixture to stand for 16 hours. Dilute with water, extract with ether and wash the organic solution with aqueous sodium hydrogen carbonate and brine. Dry the solution and evaporate to obtain a mixture of the title products as a gum (0.4 g.). Infrared absorption 2.95, 5.8, 6.05;/..

This mixture is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 32.--13/8-ethyl-3-methoxy-8-isogona- 2,5 10)-dien-17-one Dissolve 13,8 ethyl 3 methoxy-8-isogona-2,5(l0)- dien-17B-ol (1 g.) in eyclohexanone (10 cc.) and toluene (30 cc.). Add under an atmosphere of nitrogen a solution of toluene (20 cc.) and aluminium isopropoxide (0.2 g.) and reflux for 1 hour. Treat with water (20 cc.) and extract with ether. Wash the organic solution with water, dry and evaporate to obtain the title product (1 g.) as a solid; infrared spectrum 5.78, 5.9, 6.0,u.

This compound is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 3 3 .l 3 ,B-et-hyll7a-ethynyll7fi-hydroxy- 8-isogon-5 10 -en-3-one Treat a solution of l3B-ethyl-l7a-ethynyl-3-methoxy-8- isogona-2,5(10)-diien-17B-0l in alcohol (75 cc.) with oxalic acid (1.15 g.) in water (21 cc.) and allowed to stand at room temperature for 45 minutes. Add water, extract with ether and wash, dry and evaporate the organic solution. Chromatograph the product on neutral alumina and elute the product with benzene-petroleum ether to obtain the title compound, M.P. 145-155".

Infrared absorption 2.98, 3.12, 5.85,u. Found: C, 80.66; H, 9.02; C H O requires: C, 80.73; H, 9.03%.

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 34.2,3-dimethoxy-13B-methyl-8-isogona- 1,3,5(10)-trien-17-one Dissolve 2,3-dimethoxy 135 methylgona-1,3,5(10), 8,14-pentaen-17-one (2.0 g.) in ethanol (250 ml.) and add to 10% palladized charcoal (400 mg.) in ethanol (ca. 10 ml.). Shake the mixture until uptake of hydrogen ceases, when 75% of the theoretical amount will be absorbed. Filter off the catalyst. Recrystallize the residue from methanol to obtain the title compound (1.1 g.), M.P. 162168; ultraviolet absorption peaks (ethanol) at 282 m and 287 m (e=4,000); infrared maximum at 5.75 4. Recrystallize from acetone to obtain an analytical sample with M.P. 171-473". (Found: C, 76.44; H, 8.29; C H O requires: C, 76.40; H, 8.34%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 35.-13 3-isopentyl-3-methoxy-8-isogona- 1,3,5 10)-trien-l7-one Condense 6-methylheptan-2-one with diethyl oxalate in the presence of sodium ethoxidc, and convert the glyoxalate obtained by heating it with hydrochloric acid to 2-isopentylcyclopentane-1,3,5-trione, from which prepare the semicarbazone using semicarbazide hydrochloride and sodium acetate. Heat the semicarbazone with potassium hydroxide in ethylene glycol to obtain 2-isopentylcyclopentane-1,3-dione. Heat this dione (26.1 g.) with 6-(mmethoxyphenyl)-l-hexen-3-one (28.3 g.) in 0.12% methanolic potassium hydroxide (1 cc.) for hours. Cool, evaporate the solvent and dissolve the residue in ether. Wash the ether solution with aqueous sodium hydroxide, hydrochloric acid, water and dry. Evaporate the solution and treat the residue with benzene (600 ml.) and toluenep-sulfonic acid (8 g.) and reflux with continuous removal of water. Wash the cooled solution with water and evaporate to dryness. Distil the residue twice to obtain isopentyl 3-methoxygona 1,3,5(10),8,l4 pentaene-17- one (15.8 g). Hydrogenate this product (7.5 g.) in ethanol with 10% palladized charcoal until hydrogen uptake ceases. Filter the catalyst and evaporate the solvent to obtain the title compound (6.0 g.).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invent-ion.

Example 36.13p-isopentyl-3-methoxy-8-isogona- 1,3,5(10)-trien-17B-ol Reflux 13B-isopentyl 3 methoxy-8-isogona-1,3,5(10)- trien-l7-one (5.9 g.) with sodium borohydride (0.6 g.) in absolute ethanol and work up to obtain the title compound (1.3 g.) as a hemiethanolate (from ethanol), M.P. 6064.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 37.-3-methoxy-13 8-methyl-8-isogona-L3, 5( 10 ,16-tetraene-17-ol, acetate Reflux 3 methoxy 135 methyl-8-isogona-1,3,5(10)- trien-17-one (2 g.) with isopropenyl acetate (30 ml.) containing toluene-p-sulfonic acid monohydrate (0.332 g.) for 14 hrs. with slow distillation of the solvent (20 ml.). Add ether (40 ml.) to the cooled solution and wash with 5% aqueous sodium bicarbonate, water, and brine. Remove the solvent under reduced pressure and dissolve the residue in hexane (100 ml.) and chromatograph on Florex (60 g.). Elute with benzene and obtain a yellow gum (1.5 g.) which crystallizes. Recrystallize from petroleum ether to obtain the title product (0.6 g.), M.P. 84-85".

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 3 8.17B-allyloxy-3-methoxy-13 3-methyl- 8-isogona- 1,3,5( 10 -triene Suspend 3-methoxy 13/3 methyl-8-isogona-1,3,5(10)- trien-17fi-ol (3.8 g.) in sodium hydride (3.0 g. of 50% in oil) and xylene (300 ml.). Reflux for 1 hour, add allyl bromide (13.8 ml.) over a period of 1.5 hours, and reflux the reaction mixture an additional 5 hours. Add water and extract the organic layer with 2 N hydrochloric acid. Evaporate the solvent. Dissolve the residue in petroleum ether and chromatograph over neutral alumina. Elute with ether and crystallize from methanol to obtain the title compound, M.P. 96-97. (Found: C, 80.87; H, 9.27; C22H3002 requires: C, H,

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 39.--3 -methoxy-l 3B-methyl-17p-propoxy-8- isogona-1,3,5( 10)-triene Suspend 17 3 allyloxy-3-methoxy-13p-methyl-8-osogona-1,3,5(l0)-triene (1.0 g.) in alcohol (30 ml.) and bydrogenate at 1 atmosphere in the presence of 10%-palladized charcoal (300 mg.) until hydrogen uptake ceases. Filter off the catalyst and evaporate the solvent. Crystallize the residue from methanol to obtain the title compound, M.P. 96-98. (Found: C, 80.68; H, 9.83; C l-1 0 requires: C, 80.44; H, 9.83%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 40.t-Ctl'iynyl- 1 3/3-methyl-8-isogona- 1,3,5(l0) trien-3,17-dio1 Dissolve 3-hydroxy-l3fi1-methyl-8-isogona-l,3,5(10)-trien-17-one (0.8 g.) in tetrahydrofuran (15 ml.) and add Example 41.17a-ethynyl-3-methoxy-13fi-rnethyl-8- isogona-1,3,5()-trien-17-ol Add 3-methoxy-1 3 8-methyl-8-isogona- 1, 3,5 10) -trienl7-one (0.5 g.) in toluene ml.) to a solution of potassium (0.6 g.) in tert-amyl alcohol (15 ml.) and pass acetylene through the solution for 48 hours. Add Water and isolate the product with ether. Chromatograph on alumina g.). Elute unchanged starting material with benzene and the title compound with benzene ether (3 :2) 292 mg, M.P. 135-137.

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 42.--17a-ethyl-3-methoxy-13B-methyl-8- isogona1,3,5 10) -trien-17-ol Hydrogenate 17ot-ethynyl-3-methoxy-13B-methyl-8-isogona-1,3,5(10)-trien-17-ol (0.292 g.) in dioxane (10 ml.) with a 5% palladized charcoal catalyst until uptake of hydrogen ceases (49 ml. absorbed). Filter the catalyst and evaporate the filtrate to give the title compound (0.28 g.).

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 43.-17a-ethyl3-methoxy-13,8-methyl-8- isogona-2,5(10)-dien-17-ol Dissolve 17a ethyl-3-methoxy-13B-methyl-8-isogona- 1,3,5(10)-trien-17-ol (0.28 g.) in tetrahydrofuran (6 ml),

ether (14 ml.), and liquid ammonia (60 ml). Stir and add lithium (0.3 g.) Treat with ethanol (4 ml.) over a 10-minute period to discharge the blue color. Add water and extract the mixture with ether. Wash, dry, and evaporate the ethereal solution to obtain the title compound (0.24 g.); infrared maxirna at 2.85, 5.9, 6.071..

This compound is useful as an intermediate (for preparing the novel compositions of this invention which have hormonal activity. 1

Example 44.3-methoxy-1 3 3-methy1-8-isogona-2,5( 10) Y dien- 175-01 Dissolve 3 rmethoxy-13B-methyl-8-isogona-1,3,5(10)- trien-17fi-ol (28 g.) in liquid ammonia (1 l.)-tetrahydrofuran (300 ml.) and reduce with lithium (18 g.) and ethanol. Recrystallize the product from ether to obtain the title compound (18 g. M.P. 143-147", 11 max. '3472, 1695 and 1669 cm. (Found: C, 79.0; H, 9.4; C H O requires: C, 79.1; H, 9.8%.) Concentrate the mother liquors to obtain further product (3.0 g.), M.P. 140-143.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 45 .3 -methoxy- 1 3 B-methyl-8-isogona-2,5 10) dien-17-one Dissolve 3-methoxy-l3fi-methyl 8 isogona-2,5(10)- dien-17B-ol (20 g.) in toluene (1.3 l.)-cyclohexanone (283, ml.) containing aluminum isopropoxide (16.7 g.). Reflux for 3 hours under nitrogen. ,Recrystallize the product from aqueous methanol to obtain the title compound, M.P. 'l06 -lll (after softening at 9496 v max. 1724, 1695, and 1667 cm.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 46.l7a-ethynyl-3-methoxy-13fi-methyl-8- isogona-2,5(10)-dien-17/3-ol Saturate dimethylacetamide (1 l.) with acetylene. While slowly bubbling acetylene through the saturated solution, add 3-methoxy-13B-methyl-8-isogona-2,5(10)+ dien-17-one (10 g.) and lithium acetylideethylenediamine complex (13.9 g.) and stir for 2 hours at room temperature. Add the mixture to crushed ice-ammonium chloride. and extract with ether. Recrystallize the product from methanol to obtain the title compound (8 g.), M.P. 174- 182, 11 maX. 3401, 3205, 1695, and 1667 cm.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 47.-l7p-hydroxy-13fl-methyl-8-isogon-5 (10)- en-3-one, cyclic ethylene acetal Add 3.6 g. 3-methoxy-13fi-methyl-8-isogona-2,5(10)- dien-17fl-ol in 40 ml. benzene to a mixture of 0.36 g. ptoluenesulfonic acid and 7.2 ml. ethylene glycol in 70 ml. benzene, and reflux for 20 hours, using a Dean-Stark trap. Cool, wash with saturated sodium bicarbonate solution, water, and brine, and dry over sodium sulfate. Evaporate to obtain 3.6 g. of title compound, M.P. 118-123. IR 3.05, 9.1, 9.45

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 48.-13,3-methyl-8-isogon-5 10)-ene-3,17-dione, cyclic 3-ethylene acetal Dissolve 0.69 g. l7fi-hydroxy-13fi-methyl-8-isogon- 5(10)-en-3-0ne, cyclic ethylene acetal, in 10 ml. pyridine and add 0.6 g. chromium trioxide with cooling. After letting stand for 20 hours at room temperature, add 10 ml. ethyl acetate and filter through a short column of alumina (10 g.). Evaporate and crystallize from ethanol to obtain 0.56 g. of title compound, M.P. l39-148. IR 5.75, 9.0

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 49.-l7a-ethynyl-17-hydroxy- 13 fi-methyl-S- isogon-5(10)-en-3-one, cyclic ethylene acetal Add 0.56 g. 13;8-methyl-8-isogon-5(10)-ene-3,17-dione, cyclic 3-ethylene acetal, in 20 ml. toluene to a stirred solution of 0.56 g. potassium in 20 ml. t-amyl alcohol in an atmosphere of nitrogen. Pass a purified stream of acetylene through the mixture for 20 hours. Add water, extract with ether, wash with water, and dry. After evaporation, dissolve in 5 ml. benzene and absorb on 50 g. alumina. Elute with 60-80 light petroleum containing increasing amount of benzene. Petroleum-benzene (1:9) and benzene elute unchanged ketone (0.16 g.). Benzeneether (6:4) elutes 0.26 g. of title compound, M.P. 168- 170, after recrystallization from light petroleum. IR 2.93, 3.1, 9.5a.

This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 50.17a-ethynyl-l3B-methyl-8-isogon-5- ene-3,17B-diol Reduce 0.85 g. 17u-ethnyl-17 3-hydroxy-13fi-methyl-8- isogon-5(10)-en-3-one with 0.3 g. sodium borohydride in 50 ml. methanol. Recrystallize from ether to obtain 0.5 g., of title compound, M.P. 193-203.

Calcd for: C H O C, 79.95; H, 9.33%. Found: C, 79.05; H, 9.33%.

This compound has pr-ogestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Treat a solution of 17a-ethyl-13fi-methyl-3-methoxy-8- isogona-2,5(10)-dien-17-ol (0.24 g.) in methanol (10 ml.) with hydrochloric acid (0.6 ml.) and water (0.5 ml.). Allow the mixture to stand for 2 hours. Add water and remove most of the methanol under reduced pressure. Extract the mixture with ether and wash, dry, and evaporate the ethereal solution to give a solid (0.18 g.). Chromatograph on neutral alumina, benzene-ether (19:1) and benzene-ether (7:3). Elute a series of fractions. Combine the fractions and crystallize from methanol to obtain a mixture of 17a ethyl 17 hydroxy-l3 8-methyl-8-isogon- 5(10)-en-3-one and the title compound (about 25%), M.P. 139-164"; infrared maxima at 2.9, 6.05, 5.9

This compound has anabolic and androgenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 52.-17,8-hydroxy-13/3-methyl-8-isogon-4 [and 5(10) ]-en-3-one Stir 3-methoxy-13fl-methyl-8-isogona-2,5( 10) -dien-17,6- 01 (0.35 g.) with methanol (20 ml.) and 6 N hydrochloric acid (10 ml.) for 30 minutes. Add water and extract the mixture with ether. Wash, dry, and evaporate the ethereal solution. Recrystallize the residue from ethyl acetatehexane to obtain a mixture of 17B-hydroxy-13B-methyl- 8-isogon-4[and 5(10)]-en-3-one (0.182 g.), M.P. 110- 158, 11 max. 3350, 1700, and 1655 cmf This compound has anabolic and androgenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 53.-l7ix-ethynyl-17l3-hydroxy-13fl-methyl- 8-isogon-4land 5 10) -en-3-0ne Dissolve 17a ethynyl-17-hydroxy-13,6-methyl-8-isogon- 5(l0)-en-3-one (0.3 g.) in methanol (36 ml.)-concentrated hydrochloric acid (2.4 ml.)-water (1.6 ml.). Stir under nitrogen for 3 hours to obtain a total crude crystalline product with infrared absorption bands of comparable intensities at 1704 and 1653 CIIl. Recrystallize from ethyl acetate to obtain crystals of 17a-ethynyl-17- hydroxy 13B methyl l7-hydroxy-l3,8-methyl-8-isogon- 4-en-3-one (0.15 g.), M.P. 180-192", 11 max. 3367, 3215, 2083, 1701, and 1650 cmf the penultimate band being approximately twice as intense as the last band. (Found: C, 80.4; H, 8.8%.)

This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 54.-17B-hydroxy-13,8-methyl-8-isogon- 5( 10) -en-3-one Stir 3-methoxy-13,3-methyl-8-isogona-2,5 10)-dien-175- ol (1 g.) for one hour in methanol (60 ml.)-water (14 ml.) containing oxalic acid (from the dihydrate, 1.2 g.). Add saturated aqueous sodium hydrogen carbonate and extract the mixture with ether.

Recrystallize the product from ethyl acetate to obtain the title. compound (0.72 g.), M.P. 170-172, 11 max. 3350 and 1770 cm.- (Found: C, 78.8; H, 9.5. C H O requires: C, 78.8; H, 9.55%.)

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 55.17a-ethynyl-17B-hydroxy-13 8-methyl- 8-isogon-5(10)-en-3-one Dissolve 17a ethynyl-17-hydroxy-13,8-methyl-8-isogon- 5(10)-en-3-one, cyclic ethylene acetal in t-amyl alcohol 10 ml.)-toluene l ml.)- N hydrochloric acid (40 ml.) and reflux for minutes. Evaporate the organic solvents, add water, and extract the mixture with ether-ethyl acetate. Chromatograph the product on neutral alumina to obtain 24 the title compound (0.39 g.), M.P. l190, 11 max. 3378, 3215, 2083, 1704, and 1642 (weak) cmr This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 56.--17a-ethynyl-l7-hydroxy-13fi-methyl- 8-isogon-5( l0 -en-3-one Example 57.3s, 17/3-dihydroxy-17-ethynyl-13fi-methyl- 8-isogon-5 10)-en, 3-acetate Dissolve 17a-ethynyl-17-hydroxy-l3 8-methyl-8-isogon- 5(10)-en-3-one (500 mg.) in methanol (50 ml.) and reduce with sodium borohydride (200 mg.). Pour into brine, extract with ether, dry over sodium sulfate, and remove solvents. Dissolve the crystalline product in pyridine (5 ml.) and add acetic anhydride (5 ml.). Stir at room temperature for 20 hours. Add water'and extract into ether. Wash the organic layer successively with water, 10% hydrochloric acid, water, saturated sodium bicarbonate solution, and water. Dry the organic solution and remove the solvent. Crystallize the remaining gum from ether-hexane to obtain the title compound mg.), M.P. -174; ultraviolet spectrum showing no selective absorption; infrared maxima (potassium bromide) at 2.90, 3.11, 5.80, 7.93, 9.03, 9.23 1; infrared maxima (carbon disulfide) at 2.81, 3.06, 5.75, 7.85, 8.04, 9.57,u. (Found: C, 77.09; H, 8.62. C H O requires: C, 77.15; H, 8.83%.) Evaporate the ether-hexane mother liquors to obtain a fraction of title compound with M.P. 117-127" (no depression of M.P. of major fraction); infrared maxima (potassium bromide) at 3.06, 3.11; 3.80, 7.93, 8.05, 9.04, 9.75 1; infrared maxima (carbon disulfide) at 2.81, 3.06, 5.76, 7.85, 8.05, 9.58,u..

This compound has progestational activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 58.17B-(Z-dimethylaminoethoxy) -3-methoxy- 13-propyl-8-isogona-1,3,5(10)-triene To a suspension of 3-methoxy-13B-propyl-8-isogona- 1,3,5(10)-trien-17fl-ol (3.14 g.) in benzene (15 ml.), add sodamide (860 mg.) in benzene (15 ml.) and reflux for two hours. Cool reaction mixture, add Z-dimethylaminoethyl chloride hydrochloride (1.58 g.), and reflux for 16 hours. Pour reaction mixture over ice, make acidic with hydrochloric acid (10%), and extract suspension with ether. Make suspension basic with sodium hydroxide (15%) and extract with ether. Separate the ether layer, wash, and dry. Evaporate solvent to obtain a residue. Recrystallize from aqueous methanol to obtain the title compound (500 mg), M.P. 75-76"; infrared spectrum showing no hydroxyl group, ultraviolet absorption peak at 280 m (62,190). (Found: C, 77.52; H, 9.85; N, 3.46. C H NO requires: C, 77.29; H, 10.20; N, 3.63%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 59.17fl-( l-ethoxycyclopentyloxy) -13 3-ethyl- 3-methoxy-8-isogona-1,3,5(10)-triene Treat l3 3-ethyl-3-methoxy 8 isogona-1,3,5(10)-trien- 17/3-01 (1 g.) with cyclopentanone diethyl acetal.(5 m1. and a trace of p-toluenesulfonic acid. Warm the reaction mixture on the steam bath for one hour, then cool and make basic with pyridine. Pour into water and extract with ether. Wash and dry the ethereal solution, taking it to dryness by warming on the rotary evaporator (ultimately at .1 mm.). Treat the residue with a few drops of pyridine and crystallize from cyclohexane-hexane to obtain starting material. Triturate the mother liquor from the crystallization with acetone to obtain a solid. Recrystallize from acetone to obtain the title compound, M.P. 7981; infrared showing characteristic aliphatic ether absorption between 8.75 and 10.5,u. (Found: C, 78.55; H, 9.55. C H O requires: C, 78.59; H, 9.77%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 60.-l 3/3-ethyl-3-methoxy-17B- (tetrahydropyran- 2-yloxy) -8-isogona-1,3,5 10) -triene Dissolve 13B ethyl 3 methoxy-8-isogona-1,3,5 l) trien-l7/3-ol (500 mg.) in 2,3-dihydropyran ml.) and ether (3 ml.). Treat with 2 drops of hydrochloric acid and allow to stand for 3 days. Dilute the reaction mixture with ether, wash successively with saturated bicarbonate solution, Water, and saturated salt solution, and dry over sodium sulfate. Remove solvents to obtain a gum. Crystallize from hexane and dry over phosphorus pentoxide at .1 mm. to obtain the title compound (370 mg), M.P. 127l29; infrared maxima at 6.22, 6.32, 9.00, 9.43, 9.68, 10.25,u (no hydroxyl group remaining).

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 61 .-13B-ethyl-3-(Z-heptenyloxy) -8-isogona- 1,3,5 l0) -trien-l7fi-ol Dissolve l3fl-ethyl-8-isogona-1,3,5 l0)-trien-3,17fl-diol (2 g.) and sodium ethoxide (from 200 mg. sodium) in ethanol (30 ml.). Add l-bromohept-2-yne (5 ml.) and heat the mixture under reflux for 16 hours. Evaporate the solvent in vacuo, take up the residue in ether, wash successively with water, 2 N sodium hydroxide, water, and brine, and -dry over magnesium sulfate. Evaporate the ether to obtain a yellow oil (2.36 g.). Chromatograph on a column of Florex (150 g.). Elute with benzenepetroleum ether (3:1) and then with benzene to obtain the crude heptynyl ether as a gum (6914 mg.). To obtain the title compound, dissolve in benzene (650 ml.) and hydrogenate at atmospheric pressure over 5% palladiumbarium sulfate until one mole of hydrogen has been absorbed. Filter the catalyst and evaporate the solvent to obtain the title product.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 62.-13fl-ethyl-3-hydroxy-8-isogona1,3,5 (10)-trien-17-one, potassium sulfate Dissolve 13/8 ethyl 3 hydroxy 8 isogona 1,3,5 (l0)trien-17-one (1.013 g.- in dry pyridine (5 ml.). Add sulfamic acid (1.1 g.) and stir the mixture at 80 for 2 hours. Cool and pour into dry ether. Filter off the precipitated pyridinium salt, wash with ether, and dry over phosphorus pentoxideovernight. Add 2.6 g. to a well stirred mixture of pyridine (8.5 ml.) and 12% aqueous potassium hydroxide (15 ml.). Separate the resulting organic layer and evaporate to dryness in vacuo to obtain the title compound as a light brown solid. Wash the compound by decanting with dry ether (3 X50 ml.) and then recrystallize from methanol (150 ml.)

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

26 Example 63.13[3 ethyl 8 isogona 1,3,5(l0)- triene-3,17/3-diol, 17- acetate Heat 13,8 ethyl 8 isogona 1,3,5(10) triene 3, 17,8-diol (500 mg.) under reflux with glacial acetic acid for 5 hours. Pour the mixture into water. Extract the resulting precipitate into ether. Wash successively with water (2x100 ml.), aqueous sodium bicarbonate, and brine. Dry over magnesium sulfate and evaporate the sol- Vent. Recrystallize the residue from methanol to obtain the title compound (229 mg), M.P. 164-165 (softens at 130); ultraviolet absorption peak at 279 m (62,210), with shoulder at 285 m (62,030). (Found: C, 75.12. H, 8.36. C H O .I/ZCH OH requires: C, 74.99; H, 8.57%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 64.l3;8 ethyl 8 isogona l,3,5(10)- triene-3,17fl-diol, 3-benzoate Add 13/? ethyl 8 isogona 1,3,5(l0) triene 3,175- diol (2.0 g.) to warm 0.5 N potassium hydroxide (1140 ml.) and follow by benzoyl chloride (20 ml.). Shake the mixture for 10 minutes and :allow to stand at room temperature for 16 hours. Filter the resulting precipitate, recrystallize from aqueous ethanol, and dry over phosphorus pentoxide to obtain the title compound (2.5 g., 92%), M.P. 176-179"; ultraviolet absorption peaks at 230.5 mp. (21,800), 264 mp. (e4,450), and 273.5 m,u. (63,900). (Found: C, 79.57; H, 7.57. C; H 0 requires: C, 79.96; H, 7.74%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example .1 3B ethyl 3 methoxy 8 isogonal,3,5 10) -trien-17fi-ol, IO-undecenoate Dissolve 13/3 ethyl 3 methoxy 8 isogona 1,3,5 (10)-trien-17/8-ol (2.0 g.) in pyridine (10 ml.), benzene (15 ml.), and 10-undecenoyl chloride (3 ml.) and keep at room temperature over night. Pour the reaction mixture into ice water and acidity with 2 N hydrochloric acid. Extract the material with ether, wash the ethereal extract successively with Water and brine, and dry over magnesium sulfate. Evaaporate the solvent. Recrystallize the residue from tetrahydrofuran and methanol to obtain the title compound (1.7 g.), M.P. 52.5-55"; infrared spectrum showing no absorption at 3.0 1., strong band at 5.8Qu. (Found: C, 79.67; H, 9.88 C H O requires: C, 79.78; H, 9.94%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compound of this invention.

Example 66.--13B ethyl 3 methoxy 8 isogona- 1,3,S (10)-trien-17[3-ol, propionate Dissolve 13B ethyl 3 methoxy 8 isogona 1,3,5 (10)-trien-l7;8-ol (2.0 g.) in pyridine (10 ml.) and propionic anhydride (15 ml.). Keep over night at room temperature. Pour the reaction mixture into ice water and extract with ether. Wash the ethereal layer successively with water and brine and dry over magnesium sulfate. Evaporate the solvent. Recrystallize from methanol to obtain the title compound (1.4 g.), M.P. 77; infrared spectrum showing no remaining hydroxyl group. (Found: C, 77.38; H, 8.92. C H O requires: C, 77.49; H, 9.05%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 67.13B ethyl 3 methoxy 8 isogona 1,3,5(l0)-trien-17fi-ol, acetate Dissolve 13,8 ethyl 3 methoxy 8 isogona 1,3,5 (10)-trien-l7fi-ol (2.0 g.) in pyridine (10 ml.) and acetic anhydride 15 ml.). Keep the solution over night at room temperature. Pour the reaction mixture into ice water and acidify with 2 N hydrochloric acid. Extract with ether, wash the ethereal layer successively with Water and brine, and dry over magnesium sulfate. Evaporate the solvent. Recrystallize the residue from methanol to obtain the title compound (2.0 g.), M.P. 9597; infrared spectrum showing no remaining hydroxyl group. (Found: C, 77.38; H, 8.88. C H O requires: C, 77.15; H, 8.83%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 68.13 3 ethyl 3 hydroxy 8 isogona 1,3,5 10)-trien-l7-one, acetate Acetylate 13/3 ethyl 3 hydroxy 8 isogona 1,3,5 (10)-trien-l7-one (296 mg.) with acetic anhydride (1 ml.) in pyridine (1.75 ml.) at 100 for 1.5 hour. Extract from water with ether. Recrystallize from ethanol to obtain the title compound as pale pink needles (164 mg.), M.P. 140 1422 (Found: C, 77.21; H, 8.07. C l-1 requires: C, 77.27; H, 8.03%.) .This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 69.13/3 ethyl 3 heptyloxy 8 isogona 1,3,5(l0)-trien-17/3-ol Dissolve sodium borohydride (250 mg.) in ethanol (5 m1.) and add 13/3-ethyl-3-heptyloxy-8-isogona-1,3,5(10)- trien-l7-one. (800 mg.). Heat under reflux for 2 hours. Cool and evaporate to dryness. Treat with an excess of dilute acetic acid and extract with ether. Combine the ether extracts, successively with saturated potassium bicarbonate, water, and brine, and dry over magnesium sulfate. Evaporate the ether to obtain a colorless gum. Crystallize from methanol to obtain the title compound as fine, white needles (661 mg., 83%), M.P. 52-55"; ultraviolet absorption peaks at 278 m (52,050) and 286 m (1,880). (Found: C, 81.18; H, 10.18. C H O requires: C, 8l.20; H, 10.48%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 70.13fl-ethyl-3-heptyloxy-8-isogona- 1,3,5 10)-trien-17-one Dissolve the l3fi-ethyl-3-hydroxy-8-isogona-l,3,5 (10)- trien-17-one (2.21 g.) and sodium ethoxide (from 255 mg. sodium) in ethanol ml.) and add heptyl bromide (5 ml.). Heat the mixture under reflux for 16 hours. Evaporate to dryness, take up in ether, wash successively with 2 N sodium hydroxide, water, and brine, and dry over magnesium sulfate. Evaporate in vacuo to obtain a pole red gum which will crystallize slowly upon standing. Recrystallize from ethanol to obtain the title compound as fine, colorless needles (1.37 g., 48%), M.P. 44-46; ultraviolet absorption peaks at 277 m (e 2,120) and 285 ma (6 1,970). (Found: C, 81.86; H, 10.09. C H O requires: C, 81.62; H, 10.01%.)

This compound has estrogenic activity, lowers the blood lipid level,-and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 71.-13p-ethyl-8-isogona-l,3,5(10)-triene- 3,17fi-diol, diacetate Dissolve 13p ethyl-8-isogona-l,3,5(10)-trien-3-ol-17- one (715 mg.) in ethanol (15 ml.) and sodium borohydride (35.0 mg.) and heat under reflux for 90 minutes. Evaporate the solution to dryness, add water and ether, and acidify the mixture with glacial acetic acid. Separate the ethereal layer, wash successively with saturated potassium bicarbonate and brine, and dry over magnesium sulfate. Evaporate the solvent. Recrystallize the residue twice from methanol to obtain the dial (529 mg., 74%), M.P. 2l7219. Acetylate 246 mg. wath acetic 23 anhydride (1 ml.) in pyridine (1.5 ml.) at 100 for 1.5 hour. Extract the crude product from water with ether. Recrystallize from ethanol to obtain the title compound as a white solid (255 mg., M.P. 1285-1295"; ultraviolet absorption peaks at 273.5 m (6 800) and 266.5 my. (2 780). (Found: C, 74.59; H, 7.96. C H 0 requires: C, 74.56; H, 8.16%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 72.-13/3-ethyl-17 8-(2-hydroxyethoxy)-3- methoxy-8-isogona-1,3,5(10)-triene Dissolve the l3B-ethyl-3-methoxy-8-isogona-1,3,5(l0)- trien-17-one, cyclic ethylene acetal (3.42 g.) in anhydrous ether and react for 2 hours with a solution of aluminum chloride (2.66 g.), anhydrous ether (20 ml.), and 1 M lithium aluminum hydride (5 ml.) in ether. Acidify the reaction mixture with 2 N sulfuric acid and extract with ether. Treat the crystalline product with methanolic hydrochloric acid. Evaporate and recrystallize from alcohol to obtain the title compound (2.0 g.), M.P. 110-111"; infrared maximum at 2.95;, ultraviolet absorption peak at 278 m (e 2,490). (Found: C, 76.95; H, 9.15. C H O requires: C, 76.60; H, 9.36%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 73.-l3fi-ethyl-l7fi-(2-hydroxyethoxy)-3-methoxy-8-isogona-l,3,5(10)-triene, methanesulfonate Dissolve 13/8-ethyl- 1718- 2-hydroxyethoxy -3-meth0xy- 8-isogona-l,3,5(10)-triene (7.0 g.) in pyridine (47 ml.) and cool in a 'Dry Ice-acetone bath. Add mesyl chloride (2.8 g.) while stirring over a 2 hour period. Continue stirring at 25 over night. Add water, and filter off the resulting precipitate. Recrystallize from methanol to obtain the title compound (6 5.5 g.), M.P. 97; ultraviolet absorption peak at 279 m (6 2,210); infrared spectrum showing no remaining hydroxyl group. (Found: C, 65.66; H, 7.98; S, 7.60. C H O requires: C, 65.37; H, 8.11; S, 7.60%.)

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 74.-1 3fi-ethyll 7 3- 2-fluoroethoxy -3-methoxy-8 -isogona- 1 ,3 ,5 l0 -triene Dissolve 13,8-ethyl-17;?-(Z-hydroxyethoxy)-3-methoxy- 8-isogona-1,3,5(10)-triene (2.5 g.) in methylene chloride (48 ml.) and treat with 2-chloro-l,1,2-trifluoro-triethylamine (2.4 ml.). Allow to stand for 20 hours at room temperature. Wash successively with ice water, sodium bicarbonate solution, and brine. Dissolve the crude product in a solution of methanol (75 ml.), ethanol (75 ml.), potassium hydroxide (500 mg), and water (2 ml.). After 20 hours, dilute the reaction mixture with water, acidify with 2 N hydrochloric acid, and chromatograph the resulting precipitate over neutral alumina (grade I). Elute with ether-benzene and crystallize the eluate with methanol to obtain the title compound (500 mg.), M.P. 102- 104". (Found: C, 76.41; H, 9.21. C H O F requires: C, 76.36; H, 9.02%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 75 .l3 ,B-ethyl-3 -methoxy-l7fi-(2-piperidinoethoxy)-8-isogona-l,3,5(10)-triene Dissolve l3/3-ethyl-17,3-(2-hydroxyethoxy)-3-methoxy- 8-isogona-l,3,5(10)-triene, methanes'ulfonate (4.0 g.) in piperidine ml.) and reflux for 18 hours. Evaporate the solvent and dissolve the residue in 10% acetic acid ml.). Extract the acidic solution with ether, basify the aqueous layer with 10% sodium hydroxide, and again extract with ether. Wash the ethereal-solution successively with water and brine and dry over magnesium sulfate. Evaporate the solvent. Recrystallize the residue from methanol-water to obtain the title. compound (2.1 g.), M.P. 82-83". (Found: C, 78.87; H, 9.73; N, 3.38. C H O N requires: C, 78.78; H, 10.04; N, 3.40%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 76.-17,3-ethoxy-13 8-ethyl-3-methoxy-8-isogona- 1,3,5 -triene Suspend 13B-ethyl-3-methoxy-8-isogona-1,3,5 10) -trien- 1718-01 (5.0 g.) in xylene (100 ml.) and sodium hydride (3.83 g. of 50% in oil). Reflux for 1.5 hour under nitrogen. Add ethyl iodide (14.5 ml.) over a period of 4.5 hours while stirring. Continue refluxing over night. Pour the reaction mixture over ice, acidify with 2 N hydrochloric acid, and extract with benzene. Wash the organic layer with saturated sodium bicarbonate solution and dry over magnesiumsulfate. Remove the solvent. Recrystallize the residue from absolute alcohol (25 ml.). Purify over alumina (neutral grade I). Elute with benzene, evaporate to dryness, and recrystallize from methanol-water to obtain the title compound (4.1 g.), M.P. 89-91; ultraviolet absorption peak at 278 m (2,120), infrared spectrum showing no remaining hydroxyl group. (Found: C, 80.53; H,

C22H3202 requires: C, H,

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 77.-17/3-allyloxy-13,3-ethyl-3-methoxy- 8-isogona-1,3,5( 10) -triene Dissolve 13fl-ethyl-3-methoxy-8-isogona-1,3,5 (10)-trien- 175-01 (5.0 g.) in xylene (100 ml.). Reflux for 30 minutes under a Dean-Stark water separator. Add sodium hydride (3.0 g. of 50% in oil). Reflux, with stirring, for 1.5 hour. Add allyl bromide ml.) during a 3-hour period. Reflux the reaction mixture over night. Cool, acidify with hydrochloric acid (10%), add water, and extract the product (7 g.) with benzene. Dissolve the crude product in hexane and separate from the oil on an alumina column. Elute with ether. Recrystallize successively from methanol and then hexane to obtain the title compound (3.6 g.) M.P. 80-81"; ultraviolet absorption peak at 279 m (e2,()90); infrared spectrum showing no remaining hydroxyl group. (Found: C, 81.41; H, 9.63. C H O requires: C, 81.13; H, 9.47%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 7 8 .--l 3 fi-ethyl-3-methoxy-17fl-propoxy- 8-isogona- 1,3,5 10 -triene Dissolve l7fl-allyloxy-13/3-ethyl-3-methoxy-8-isogona-1, 3,5 10)-triene (1.8 g.) in benzene (100 ml.). Hydrogenate at 1 atmosphere in the presence of 10% palladized charcoal (600 mg.) until hydrogen uptake ceases. Filter Off the catalyst and evaporate the solvent. Recrystallize from hexane to obtain the title compound (700 mg), M.P. 95- 98. (Found: C, 80.84; H, 9.94. C H O requires: C, 80.64; H, 10.01%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 79.-3-allyloxy-13fi-ethyl-8-isogona-1,3,5(10)- trien-17B-ol Dissolve 13 B-ethyl-8-isogona-1,3,5 (10)-triene-3,l7fl-diol (1.01 g.) and sodium ethoxide (from 106 mg. sodium) in ethanol (10 ml.). Add allyl bromide (0.5 ml.) and heat the mixture under reflux for 15 .minutes. Add more allyl bromide (1 ml.) and continue refluxing for 90 minutes. Evaporate to dryness, take up the product in di-isopropyl ether, wash the ethereal layer successively with 10% sodium hydroxide, water, and brine, and dry over magnesium sulfate. Evaporate the solvent in vacuo. Recrystallize the residue from methanol to obtain the title compound (510 mg., 44%), M.P. 7779; ultraviolet absorption peaks at 277 m (e1,990) and 285 m (61,870). (Found: C, 80.70; H, 9.24. C H O requires: C, 80.93; H, 9.26%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 80.l-3/3-ethyl-l6-hydroxymethylene-3-meth0xy- 8-isogona-1,3,5(10)-trien-17-one Dissolve 13B ethyl 3 methoxy-S-isogona-l,3,5(l0)- trien-17-one (5.0 g.) in benzene (50 ml.) and treat with 30 ml. ethylformate (distilled over phosphorus pentoxide) and 1.7 g. of sodium methoxide. Reflux the reaction mixture for 2 hours, then allow to stand over night at room temperature. Pour over ice and extract with ether. Acidify the aqueous layer with 10% hydrochloric acid, extract with ether, Wash the organic layer with brine, and dry over magnesium sulfate. Evaporate the solvent. Recrystallize the residue from acetone-water to obtain the title compound (2.6 g.), M.P. l47l52. (Found: C, 77.01; H, 7.81. C H O requires: C, 77.27; H, 8.03%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 8 1 .l 3,3-ethyl-16e-fluoro-3-methoxy-8-isogonal,3,5(10)-trien-17-one Dissolve l3fi-ethyl-l6-hydroxymethylene-3-methoxy-8- isogona-l,3,5(10)-trien-l7-one (1.5 g.) in tert-butyl alcohol (50 ml.) and combine with a solution of potassium (0.8 g.) in tert-butyl alcohol (100 ml.). Add dropwise, while stirring continuously over a 5-minute period, a solution of potassium (0.4 g.) in tert-butyl alcohol (50 ml.). Simultaneously pass perchloryl fluoride through this reaction mixture for a total of 15 minutes. Pour reaction mixture over ice and allow to stand over night. Extract mixture with ether. Wash organic layer successively with sodium hydroxide (10%) solution, hydrochloric acid (5%) solution, and saturated sodium bicarbonate solution. Dry the washed organic layer over magnesium sulfate. Evaporate the solvent and recrystallize the residue from methanol to yield a product (900 mg.) which is a 50/ 50 mixture of 13,8-ethyl-16,16 difluoro 3 methoxy-8-isogona-1,3,5 (10)-trien 17 one and the title compound; infrared maxima at 5.65, 5.71,u.. (Found: F, 8.7; a 50/50 mixture of mono and difluorosteroids requires: F, 8.7%

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this solution.

Example 82.-13,8-ethyl-16,l6-difluoro-3-methoxy-8- isogona-1,3,5(10)-trien-17fl-ol Dissolve 13fl-ethyl-16,16-difluoro-3-methoxy-8-isogona- 1,3,5(10)-trien-17-one (800 mg.) in tetrahydrofuran ml.). Stir well. Cool the solution in an ice water bath and, at the same time, add lithium aluminum tri(tertiarybutoxy)hydride (2.4 g.) in tetrahydrofuran (20 ml.).- Allow to stand at room temperature over night. Mix with Water, neutralize with acetic acid, and extract with ether. Wash the organic layer with a saturated sodium bicarbonate solution and dry over magnesium sulfate. Evaporate the solvent. Recrystallize the residue from methanol to obtain a mixture (apparently 50: 50) of the title compound with the corresponding monofluoro compound (260 mg.), M.P. 149-151"; infrared maxima at 2.9 (Found: F, 8.2%; 50/ 50 mixture requires: F, 8.6%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 83.l 3B-ethyl-3-methoXy-8-isogona-1,3,5( l0) tiene-16,17-dione, 16-oxime Stir 13 p-ethyl-3 -methoxy-8-isogona-1,3,5 (10)-trien-17- one (6.8 g.) with a solution of potassium tert-butoxide (from the metal 1.7 g.) in tert-butanol (70 ml.) for hours, and then add isoamyl nitrite (5.1 ml.) and stir for 16 hours. Warm to 50 for 2 hours, and then cool and pour into ice-water and extract with ether. Acidity the aqueous solution wih acetic acid and extract with ether. Wash and dry the ethereal extracts, evaporate and recrystallize the residue from ether, ethyl acetate and methanol to obtain the title compound (2.4 g.) M.P. 202203.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 84.-13B-ethyl-3-methoxy-17;3-hydroxy 8 isogona-1,3,5 )-trien-16-one Stir a suspension of 13fl'ethyl-3-methoxy-8-isogona-1,3, 5(10)-trien-16,17-dione, 16-oxime, with acetic acid (90 ml.) and water (5.4 ml.) containing zinc dust (7.2 g.) for 30 minutes at 45 when dissolution of the steroid is complete. Add water (81 ml.) and reflux for 1 hour and then cool to Decant the aqueous liquid and wash the zinc with benzene. Combine the aqueous and benzene washings and treat with 1.5 N sodium hydroxide (690 ml.) and ether (300 ml.). Separate and wash the organic layer with 5 N hydrochloric acid, 5% aqueous sodium carbonate and water. Dry and evaporate the solvent and chromatograph the residue on silica gel. Recrystallize the solid fractions from ethyl acetate to obtain the title product (0.1 g.) M.P. 123-132.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 85 .3- 2-diethylaminoethoxy)-1 3 fiethyl-S-isogona-1,3,5(10)-trien-17fl-0l Add 13f3-ethyl-8-isogona-1,3,5(10)-triene 3,1713 diol (587 mg, 2.06 m. mole) and diethylaminoethyl chloride hydrochloride (4.5 mg., 2.6 m. mole) to a solution of sodium (100 mg., 4.3 m. mole) in dry ethanol (20 ml.). Heat the mixture under reflux for 2 hours. Evaporate the solvent in vacuo. Treat the residue with water and extract with ether. Extract the ethereal solution with dilute hydrochloric acid and basify the aqueous phase with dilute sodium hydroxide. Extract the mixture with ether, wash the extracts successively with water and brine, and dry over magnesium sulfate. Evaporate the solvent to dryness. Dissolve the residue in dry ether. Add alcoholic hydrogen chloride to precipitate the title compound as the hydrochloride (298 mg., 34% Recrystallize from ethanol-ether to obtain white needles, M.P. 234-235 ultraviolet absorption peaks at 275.5 ma (e1,720) and 283 m (1,665). (Found: C, 70.76; H, 9.45; N, 3.46. C H NO Cl re quires: C, 71.14; H, 9.55; N, 3.32%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 86.2-diethylaminomethyl-13B-ethyl-3-hydroxy- 8-isogona-1,3,5(10)-trien-l7-one Dissolve 13B-ethyl-8-isogona-1,3,5(10)-trien-3-ol 17- one (4.0 g.) and diethylamine (20 ml.) in ethanol (100 ml.), benzene (60 ml.), and 40% formaldehyde (12 ml.). Heat under reflux for 16 hours. Evaporate the mixture under reduced pressure, dilute with water, and extract with ether. Combine the ethereal extracts and treat with 10% hydrochloric acid. Basify the resulting aqueous layer with aqueous ammonia. Extract the mixture with ether, combine the extracts, and dry over magnesium sulfate. Evaporate the solvent to obtain a pale red gum. Dissolve the gum in dry ether and treat with dry hydrogen chloride. Stir at 0 for one hour. Filter off the title compound as the hydrochloride (4.95 g., 87%). Recrystallize from ethanol-ether to obtain the title product as fine, white needles, M.P. 230-231; ultraviolet absorption peak at 287.5 mg. (63,200)- (Found: C, 67.89; H, 8.84; Cl, 8.14. C H NO CL H O requires: C, 67.97; H, 9.03; CI, 8.36% To obtain the free base, dissolve the hydrochlo- 32. ride in water (30 ml.) and treat with 10% sodium hydroxide. Wash and dry the resulting white precipitate.

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 87.13fl-isopropyl-3-methoxy-8-isogona 1,3,5 (10)-trien-17-one Dissolve 1.0 g. of 13fl-isopropyl-3-methoxygona-1,3,5 (10)8,14-pentaen-17-one in ethanol and hydrogenate in the presence of 10% palladized charcoal (0.5 g.) until hydro'gen uptake ceases. Work up in the usual manner. Crystallize twice from methanol to obtain the title compound (430 mg.) M.P. 123-214"; ultraviolet absorption peak at 278 m (51,875).

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 88.-13B-butyl-3-methoxy-8-isogona-l,3,5(10)- trien-17fi-ol Example 89.13}9,17-diethyl-3-methoxy-8-isogona 1,3,5 (l0)-trien-l7/3-ol Suspend 13,B-ethyl-17-ethyny1-3-methoxy-8-isogona-1,3, 5(10)-trien-17;3-ol (2.0 g.) in methanol (310 ml.) and hydrogenate in the presence of 10% palladized charcoal (700 mg.) until hydrogen uptake ceases. Filter, remove solvent, crystallize, and sublimate to obtain the title compound (500 mg.), M.P. 131-134. (Found: C, 80.11; H, 9.56. C H O requires: C, 80.44; H, 9.83%.)

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 90.17-(3-diethylamino 1 h propynyl) 13 9- ethyl--3-methoxy-8-isogona-1,3,5 l0)trien-17,6-ol

Suspend 13 8-ethy1-17-ethynyl-3-rnethoxy-8-isogona-1,3, 5(l0)-trien-17B-ol (5.4 g.) in a solution of dioxane (40 ml.), water (3.1 ml.), formalin (3.0 ml. of a 40% aqueous solution), diethylamine (2.8 ml.), glacial acetic acid (1.3 ml.), and cuprous chloride mg.). Stir for 22 hours at 60". Pour the reaction mixture onto ice and basify with 2 N sodium hydroxide to pH 10.0. Filter off the product and recrystallize from ethyl acetate-hexane to obtain the title compound (550 mg), M.P. 141-142. (Found: C, 79.23; H, 9.41; N, 3.33. C H O N requires: C, 79.11; H, 9.60; N, 3.42%.)

This compound has estrogenic activity, lowers the blood lipid level, and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 91.13fi-ethyl-17-ethynyl-3-methoxy-8-isogona- 1,3,5(10)-trien-17fl-ol Dissolve 13,3 ethyl-3-methoxy-8-isogona-1,3,5(10)- trien-17-one (10 g.) in 300 ml. of dimethylacetamide. Saturate with acetylene for 45 minutes and then add lithium acetylide-ethylenediamine complex (15.9 g.). Stir the mixture for 4 hours under acetylene. After 15 hours pour the reaction mixture on ice and extract with ether. Wash the ether layer with water, brine, and dry over magnesium sulfate. Evaporate the ether and recrystallize twice from methanol-water to obtain the title compound 33 (6.4 g.), M.P. 139140.5; infrared maxima at 2.9, 3.1;/.. (Found: C, 81.06; H, 8.63. czzHzgo z requires: C, 81.44; H, 8.70%.)

This compound has estrogenic activity and is useful asan intermediate for preparing the hormonal compounds of this invention.

Example 92.-13p-ethyl-3-methoxy-8-isogona-2,S(l0)- dien-l7-one, cyclic ethylene acetal To a solution of 2 g. lithium metal in 400 ml. of liquid ammonia, add 50 ml. of tetrahydrofuran and a solution of 2 g. 13fl-ethyl-3-methoxy-8-isogona-l,3,5(10)-trien-17- one, cyclic ethylene acetal in 50 ml. of tetrahydrofuran. Stir for 2 hours, add 40 ml. of ethanol during 25 minutes, and extract with ether. Wash, dry, and evaporate to obtain a gum, crystallize with hexane to obtain 1.4 g. product, M.P. l23-126. Recrystallize from methanol to obtain analytical sample, M.P. 127-130. IR 5.44, 5.98

Calcd for C H O C, 76.70; H, 9.30%. Found: C, 76.63; H, 9.29%.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 93 .-1 7 8-ethoxyl 3 ,B-ethyl-3-methoxy- 8-isogona-2,5 10) -diene Dissolve 17 8 ethoxy-l3B-ethyl-3-methoxy-8-isogona- 1,3,5(10)-triene (2.5 g.) in l-methoxy-Z-propanol (70 ml.), tetrahydrofuran (125 ml.), and liquid ammonia (220 ml.) and treat with lithium (2.5 g.). Add ammonium chloride (25.0 g.) and water. Filter off the title compound (2.1 g.).

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 94.-13/3-ethyl-17u-ethynyl-3 -methoxy- 8-isogona-2,5 10) -dien- 1713-01 Example 95 .-17B-ethoxy- 1 3fi-ethyl-8-isogon- -en-3-one Dissolve 17B ethoxy-l 3p-ethyl-3-methoxy-8-isogonal,3,5(1'0)-triene (2.5 g.) in l-methoxy-Z-propanol (70 ml.), tetrahydrofuran (125 ml.), and liquid ammonia (220 ml.). Treat with lithium (2.5 g.). Add ammonium chloride (25.0 g.), then water. Filter off the resulting 17fl-ethoxy 13/3 ethyl-3-methoxy-8-isogona-2,5(10)- diene. Add, while stirring under nitrogen, a solution of methanol (210 ml.), oxalic acid monohydrate (3.0 g.), and water (35 ml.). After 3 hours, precipitate with water and extract with ether. Recrystallize from petroleum ether to obtain the title compound (1.4 g.), M.P. 94.5-96.5"; infrared maximum at 5.84,. (Found: C, 79.73; H, 10.11. C H O requires: C, 79.70; H, 10.19%.)

This compound has anabolic and androgenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention. 1

Example 96'.13,8-ethyl-l7fi-hydroxy-8-isogon-5 10) -en- 3-one, cyclic ethylene acetal Reflux l3-ethyl-3-methoxy-8-isogona-2,5(10)-175-01 (1 g.) with toluene-p-sulfonic acid (0.1 g.) in benzene (50 cc.) and ethylene glycol (2 cc.) for 18 hours with continuous removal of water. Add ether to the cooled reaction mixture and wash with aqueous sodium hydrogen carbonate, water, and dry. Evaporate the solvent to obtain the title compound.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 97.13B-ethyl-8-isogon-5 (10)-en3,17-dione, 3-cyclic ethylene acetal Dissolve 13,8 ethyl-17fl-hydroxy-8-isogon-5(10)-en-3- one, cyclic ethylene acetal (1. g.) in pyridine (15 cc.) and add chromium trioxide (1 g.) with cooling. Allow the mixture to stand for 20 hours at 25, and then add ethyl acetate and filter through a short column of alumina (20 g.). Evaporate the solvent to obtain the title compound; infrared absorption peak at 5.75

This compound is useful as an intermediate for preparing the novel compounds of this invention which have hormonal activity.

Example 98.l7a-ethynyl-13,6-ethyl-17-hydroxy-8- isogon-S (10)-en-3-one, cyclic ethylene acetal Example 99.13-ethyl-17a-ethynyl-17-hydroxy-8- isogon-S 10) -en-3-one Dissolve 17a-ethynyl-13 8-ethyl 17 hydroxy-8-isogon- 5(10)-en-3-one, 3-cyclic ethylene acetal (0.5 g.) in tertamyl alcohol (10 cc.)-toluene (10 cc.)-5N-hydrochloric acid (40 cc.) and reflux for 10 minutes. Separate the organic layer and evaporate to dryness. Chromatograph the residue on neutral alumina to obtain the title product, M.P. 145-150".

This compound has estrogenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example -135, 17a-diethyl-3-methoxy-8-isogona- 2,5(10)-dien-17-ol Dissolve 13fi,17a-diethyl 3 methoxy-8-isogona-2,5 (10)-dien-17-ol (0.5 g.) in 1-methoxy-2-propano1 (15 cc.), tetrahydrofuran (25 cc.) and liquid ammonia (50 cc.) and treat the stirred solution with lithium (0.7 g.). Add ammonium chloride (5 g.) and water. Filter oil the title compound; infrared absorption 5.9, 6.0a.

This compound is useful as an intermediate for preparing the novel compositions of this invention which have hormonal activity.

Example 101 .13,8, 17a-diethyl- 17-hydroxy-8-isogon- 4[and 5 10) -en-3-one Stir 13,3,l7a-diethyl 3 xmethoxy-8-isogona-2,5(10)- dien-17-ol (0.7 g.) with methanol (20 cc.) and 6 N hydrochloric acid (10 cc.) for 30 minutes. Add water and extract with ether. Wash, dry, and evaporate the ethereal solution and recrystallize the residue from ethyl acetate hexane to obtain a mixture of the title products.

This compound has anabolic and androgenic activity and is useful as an intermediate for preparing the hormonal compounds of this invention.

Example 102.-13;8-ethyl-3-pyranyloxy-8-isogona-l,3, 5 10)-trien-17-one Dissolve 13p-ethyl-3-hydroxy 8 isogona-1,3,5(10)- trien-17-one (3.2 g.) in a mixture of benzene (12 cc.), methanol (0.25 cc.), pyridine (0.4 cc.) and acetyl chlo- 

